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Liu Y, Bai H, Guan H, Wang C, Song X, Yong Z, Guo X, Li L, Zhang Z. Animal experiments and network pharmacology to explore the anti-inflammatory mechanism of dapagliflozin in the treatment of polycystic ovary syndrome. Gynecol Endocrinol 2025; 41:2454432. [PMID: 39826530 DOI: 10.1080/09513590.2025.2454432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/31/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder associated with chronic low-grade inflammation of the ovary. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of antidiabetic drugs that can reduce the weight and hyperglycemia of type 2 diabetes patients. Dapagliflozin is a highly selective, orally active and reversible inhibitor of the human SGLT2. However, the role of dapagliflozin in regulating PCOS remains unclear. METHODS In this study, 24 six-week-old female Sprague Dawley (SD) rats were randomly divided into control, letrozole, and letrozole + dapagliflozin groups. PCOS model rats were produced by gavage administration of letrozole for 21 days. The intervention was conducted after the gavage administration of dapagliflozin for 14 days to evaluate the estrous cycle and ovarian imaging changes of the rats in each group. We observed changes in the weight, ovarian weight, and ovarian morphology of the rats in each group. Pathological changes in the ovaries were examined by H&E staining, changes in ovarian tissue cell apoptosis were identified using TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and changes in inflammation-related factors were detected using immunohistochemistry and Western blotting analysis. Network pharmacology was used to predict the inflammatory targets and pathways affected by dapagliflozin in treating PCOS, and the potential interactions between dapagliflozin and inflammation-related target proteins were evaluated through molecular docking. RESULTS Our results demonstrated that dapagliflozin treatment significantly improved PCOS symptoms, recovered ovarian morphology and physiological functions, and reduced the apoptosis of ovarian cells after drug intervention. Dapagliflozin treatment also reduced the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, indicating its anti-inflammatory properties. Furthermore, network pharmacology identified 26 intersecting target genes relevant to inflammation in PCOS, with subsequent molecular docking simulations revealing strong binding affinities of dapagliflozin to key targets, including AKT1 and TP53. CONCLUSIONS These findings suggest that dapagliflozin exerts beneficial effects on PCOS by ameliorating ovarian dysfunction and reducing inflammation. Dapagliflozin represents a promising therapeutic candidate for managing PCOS, warranting further clinical investigation to explore its full potential in treating this multifaceted disorder.
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Affiliation(s)
- Yong Liu
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - He Bai
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
- Gaozhou People's Hospital, Maoming, China
| | - Huilin Guan
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Chunhua Wang
- College of Life Science and Technology, Mudanjiang Normal University, Mudanjiang, China
| | - Xueqing Song
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Zihao Yong
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaomeng Guo
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Luxin Li
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Zhen Zhang
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
- School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, China
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Amin MA, Sadik NA, Saad HA, Fawzy M, Elsheimy HA. The effect of SGLT2 inhibitors on hepatic steatosis detected by MRI-PDFF in patients with type 2 Diabetes mellitus and metabolic-associated steatotic liver disease. Intern Emerg Med 2025:10.1007/s11739-025-03902-w. [PMID: 40085410 DOI: 10.1007/s11739-025-03902-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/12/2025] [Indexed: 03/16/2025]
Abstract
Sodium-glucose co-transporter type-2 (SGLT2) inhibitors have been identified to have a crucial hepatoprotective role in patients with type 2 diabetes (T2DM) and metabolic-associated steatotic liver disease (MASLD). Thus, we aimed to assess the effect of SGLT2 inhibitors on hepatic steatosis in patients with T2DM and MASLD added to the standard of care (SOC) treatment. Our study was a single-arm clinical trial with trial no ISRCTN85961860. Thirty T2DM patients with MASLD were recruited from the outpatient endocrinology and diabetes clinic of the Internal Medicine Department at Kasr Al-Aini Hospital, Cairo University, Egypt. Our Patients received Empagliflozin 10 mg daily which was added to SOC treatment and followed up for 24 weeks. Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was done at baseline and after 24 weeks to assess the percentage change in hepatic fat mass. Also changes in Fib-4 and NAFLD fibrosis scores were calculated. Our study showed a statistically significant decrease in the mean MRI-PDFF measurement of hepatic steatosis after 24 weeks of adding empagliflozin to SOC treatment (13.297 ± 7.15) compared to the mean at baseline (15.288 ± 8.72), P = 0.006 with overall percentage decrease about 13.16% of liver steatosis. There were significant decreases in BMI, fasting blood glucose, and Alanine transaminase, (P < 0.001, 0.03, 0.01) respectively. There were no significant differences in Fib-4 or NAFLD fibrosis scores. Adding empagliflozin 10 mg to the standard treatment in patients with diabetes and MASLD could reduce hepatic fat mass significantly after 24 weeks of treatment. Thus, adding SGLT2 inhibitors to the clinical practice guidelines could be a therapeutic agent for patients with MASLD and T2DM.
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Affiliation(s)
- Mona Ahmed Amin
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt
| | - Noha Adly Sadik
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt.
| | - Hala Ahmed Saad
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt
| | - Mohammed Fawzy
- Department of Diagnostic Radiology, National Hepatology and Tropical Research Institute, Cairo, Egypt
| | - Hend Abdallah Elsheimy
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt
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Kumar N, Kumar B, Ashique S, Yasmin S, Venkatesan K, Islam A, Ghosh S, Sahu A, Bhui U, Ansari MY. A critical review on SGLT2 inhibitors for diabetes mellitus, renal health, and cardiovascular conditions. Diabetes Res Clin Pract 2025; 221:112050. [PMID: 39965722 DOI: 10.1016/j.diabres.2025.112050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).
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Affiliation(s)
- Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sumel Ashique
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.
| | - Sabina Yasmin
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Suman Ghosh
- Division of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Kolkata, West Bengal 700114, India
| | - Anwesha Sahu
- Division of Pharmacology, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Utpal Bhui
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Mohammad Yousuf Ansari
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana 133207, India; Ibne Seena College of Pharmacy, Azmi Vidya Nagri Anjhi Shahabad, Hardoi, Uttar Pradesh (U.P.) 241124, India.
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Li H, Hou Y, Xin W, Ding L, Yang Y, Zhang Y, Wu W, Wang Z, Ding W. The efficacy of sodium-glucose transporter 2 inhibitors in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis. Pharmacol Res 2025; 213:107647. [PMID: 39929274 DOI: 10.1016/j.phrs.2025.107647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/13/2025]
Abstract
The efficacy of sodium-glucose transporter 2 (SGLT-2) inhibitors for nonalcoholic fatty liver disease (NAFLD) is unclear. Therefore, we conducted a systematic review and meta-analysis to evaluate SGLT-2 inhibitors efficacy for NAFLD treatment. We systematically searched major electronic databases (PubMed, Cochrane Library, Web of Science, Embase) from inception until 11/2023, identifying randomized controlled trials (RCTs) of SGLT-2 inhibitors treatment for patients with NAFLD. The mean differences (MD or SMD) and 95 % confidence intervals (CIs) were calculated via random-effects models. Eleven articles (n = 805 patients with NAFLD) were included in this study. Of these, 408 participants received SGLT-2 inhibitors, while 397 participants were in the control group. SGLT-2 inhibitors significantly reduced liver enzyme levels, including aspartate alanine aminotransferase (ALT) (MD [95 % CI]; -9.31 U/L [-13.41, -5.21], p < 0.00001), aspartate aminotransferase (AST) (MD [95 % CI]; -6.06 U/L [-10.98, -1.15], p = 0.02), and gamma-glutamyltransferase (GGT) (MD [95 % CI]; -11.72 U/L [-15.65, -7.80], p < 0.00001). SGLT-2 inhibitors intervention was also associated with significant reductions in body weight (MD [95 % CI]; -2.72 kg [-3.49, -1.95], p < 0.00001) and BMI (MD [95 % CI]; -1.11 kg/m2 [-1.39, -0.82], p < 0.00001) and improvements in glycaemic indices, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). However, no significant changes in total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) were observed. The meta-analysis revealed a beneficial effect of SGLT-2 inhibitors on liver functions and body weight, BMI, TG, HDL-C, and glucose homeostasis in patients with NAFLD, indicating that SGLT-2 inhibitors might be a clinical therapeutic strategy for these patients, especially individuals with concurrent type 2 diabetes mellitus (T2DM).
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Affiliation(s)
- Hongsheng Li
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Yanli Hou
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Wenyong Xin
- Department of Retirement Affairs, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China
| | - Lina Ding
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Ying Yang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Yikun Zhang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Wenqi Wu
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Zhibin Wang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China.
| | - Wenyu Ding
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China.
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Xin W, Zhou J, Peng Y, Gong S, Liao W, Wang Y, Huang X, Mao Y, Yao M, Qin S, Xiong J, Li Y, Lan Q, Huang Y, Zhao J. SREBP1c-Mediated Transcriptional Repression of YME1L1 Contributes to Acute Kidney Injury by Inducing Mitochondrial Dysfunction in Tubular Epithelial Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412233. [PMID: 39680752 PMCID: PMC11809329 DOI: 10.1002/advs.202412233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/29/2024] [Indexed: 12/18/2024]
Abstract
Acute kidney injury (AKI) is a prevalent clinical syndrome with high morbidity and mortality. Accumulating studies suggest mitochondrial dysfunction as the typical characteristics and key process of AKI, but the underlying mechanism remains elusive. The YME1-like 1 (YME1L1) ATPase, an inner mitochondrial membrane protein, is screened and identified to be downregulated in renal tubular epithelial cells of various mouse models and patients of AKI. Dramatically, restoration of YME1L1 expression significantly alleviates cisplatin-induced AKI and subsequent chronic kidney disease (CKD) through attenuating mitochondrial dysfunction via maintaining optic atrophy 1 (OPA1)-mediated mitochondrial energy metabolism homeostasis. Mechanistically, the upregulated expression of sterol regulatory element binding transcription factor 1c (SREBP1c) is demonstrated to be responsible for cisplatin-mediated transcriptional inhibition of YME1L1 via directly binding to its promoter region. Moreover, cisplatin-induced methyltransferase-like 3 (METTL3)-mediated m6A modification enhances SREBP1c mRNA stability, thereby upregulating its expression. Notably, both depletion of SREBP1c and renal tubule-specific overexpression of YME1L1 markedly ameliorate cisplatin-induced AKI and its transition to CKD. Taken together, these findings suggest that METTL3-mediated SREBP1c upregulation contributes to AKI and its progression to CKD through disrupting mitochondrial energy metabolism via transcriptionally suppressing YME1L1. Targeting the SREBP1c/YME1L1 signaling may serve as a novel therapeutic strategy against AKI.
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Affiliation(s)
- Wang Xin
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Jie Zhou
- Department of OncologySouthwest Cancer CenterSouthwest HospitalArmy Medical UniversityChongqing400038China
| | - Yuzhu Peng
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Shuiqin Gong
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Wenhao Liao
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yaqin Wang
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Xixin Huang
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yang Mao
- Clinical Medical Research CenterXinqiao HospitalArmy Medical UniversityChongqing400037China
| | - Mengying Yao
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Shaozong Qin
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Jiachuan Xiong
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yan Li
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Qigang Lan
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Yinghui Huang
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
| | - Jinghong Zhao
- Department of NephrologyChongqing Key Laboratory of Prevention and Treatment of Kidney DiseaseChongqing Clinical Research Center of Kidney and Urology DiseasesXinqiao HospitalArmy Medical University (Third Military Medical University)Chongqing400037China
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Jiang B, Cheng Z, Wang D, Liu F, Wang J, Fu H, Mao J. Unveiling the podocyte-protective effect of sodium-glucose cotransporter-2 inhibitors. Kidney Res Clin Pract 2025; 44:69-78. [PMID: 39639415 PMCID: PMC11838849 DOI: 10.23876/j.krcp.24.144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/28/2024] [Accepted: 10/07/2024] [Indexed: 12/07/2024] Open
Abstract
The renoprotective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in both diabetic and nondiabetic nephropathy are widely recognized due to results from randomized controlled trials notably the DAPA-CKD and EMPA-KIDNEY trials. Research exploring the mechanisms of renoprotection indicates that SGLT2 inhibitors exert protective effects on podocytes by enhancing autophagy and stabilizing the structure of podocytes and basement membranes. Furthermore, reductions in lipotoxicity, oxidative stress, and inflammation have been confirmed with SGLT2 inhibitor treatment. Recent clinical studies have also begun to explore the effects of SGLT2 inhibitors on nondiabetic podocytopathies, such as focal segmental glomerulosclerosis. In this review, we summarize clinical and laboratory studies that focus on the podocyte-protective effects of SGLT2 inhibitors, exploring the potential for broader applications of this novel therapeutic agent in kidney disease.
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Affiliation(s)
- Buchun Jiang
- Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Zhiwen Cheng
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- Department of General Pediatrics, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongjie Wang
- Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Fei Liu
- Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Jingjing Wang
- Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Haidong Fu
- Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Jianhua Mao
- Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
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Mendez Espinoza I, Choos END, Ecelbarger CM, Shepard BD. SGLT2 inhibition leads to a restoration of hepatic and circulating metabolites involved in the folate cycle and pyrimidine biosynthesis. Am J Physiol Gastrointest Liver Physiol 2024; 327:G235-G253. [PMID: 38915277 PMCID: PMC11427092 DOI: 10.1152/ajpgi.00029.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/19/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024]
Abstract
Inhibition of sodium-glucose cotransporter 2 (SGLT2) by empagliflozin (EMPA) and other "flozins" can improve glycemic control under conditions of diabetes and kidney disease. Though they act on the kidney, they also offer cardiovascular and liver protection. Previously, we found that EMPA decreased circulating triglycerides and hepatic lipid and cholesterol esters in male TallyHo mice fed a high-milk-fat diet (HMFD). The goal of this study was to determine whether the liver protection is associated with a change in metabolic function by characterizing the hepatic and circulating metabolic and lipidomic profiles using targeted LC-MS. In both male and female mice, HMFD feeding significantly altered the circulating and hepatic metabolome compared with low-fat diet (LFD). Addition of EMPA resulted in the restoration of circulating orotate (intermediate in pyrimidine biosynthesis) and hepatic dihydrofolate (intermediate in the folate and methionine cycles) levels in males and acylcarnitines in females. These changes were partially explained by altered expression of rate-limiting enzymes in these pathways. This metabolic signature was not detected when EMPA was incorporated into an LFD, suggesting that the restoration requires the metabolic shift that accompanies the HMFD. Notably, the HMFD increased expression of 18 of 20 circulating amino acids in males and 11 of 20 in females, and this pattern was reversed by EMPA. Finally, we confirmed that SGLT2 inhibition upregulates ketone bodies including β-hydroxybutyrate. Collectively, this study highlights the metabolic changes that occur with EMPA treatment, and sheds light on the possible mechanisms by which this drug offers liver and systemic protection.NEW & NOTEWORTHY Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, have emerged as a new treatment option for individuals with type 2 diabetes that have positive impacts on kidney and cardiovascular disease. However, less is known about their impact on other tissues, including the liver. Here, we report that empagliflozin reduces hepatic steatosis that is associated with restoring metabolic intermediates in the folate and pyrimidine biosynthesis pathways. These changes may lead to new approaches to treat nonalcoholic fatty liver disease.
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Affiliation(s)
- Ileana Mendez Espinoza
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Elijah N D Choos
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Carolyn M Ecelbarger
- Department of Medicine, Georgetown University, Washington, District of Columbia, United States
| | - Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Zachou M, Flevari P, Nasiri-Ansari N, Varytimiadis C, Kalaitzakis E, Kassi E, Androutsakos T. The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. Eur J Clin Pharmacol 2024; 80:127-150. [PMID: 37938366 PMCID: PMC10781828 DOI: 10.1007/s00228-023-03586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. METHODS In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. RESULTS Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. CONCLUSION In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.
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Affiliation(s)
- Maria Zachou
- Gastroenterology Department, "Sismanoglio" General Hospital, 151 26, Athens, Greece
| | - Pagona Flevari
- Expertise Center in Rare Haematological Diseases-Haemoglobinopathies, "Laiko" General Hospital, 115 27, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | | | - Evangelos Kalaitzakis
- Department of Gastroenterology, University Hospital of Heraklion, University of Crete, 715 00, Heraklion, Greece
| | - Eva Kassi
- Unit of Molecular Endocrinology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, "Laiko" Hospital, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
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10
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Chae SY, Kim Y, Park CW. Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia. Antioxidants (Basel) 2023; 12:2083. [PMID: 38136203 PMCID: PMC10740440 DOI: 10.3390/antiox12122083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/26/2023] [Accepted: 12/01/2023] [Indexed: 12/24/2023] Open
Abstract
Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD.
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Affiliation(s)
- Seung Yun Chae
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (S.Y.C.); (Y.K.)
| | - Yaeni Kim
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (S.Y.C.); (Y.K.)
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea; (S.Y.C.); (Y.K.)
- Institute for Aging and Metabolic Disease, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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11
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Khaznadar F, Petrovic A, Khaznadar O, Roguljic H, Bojanic K, Kuna Roguljic L, Siber S, Smolic R, Bilic-Curcic I, Wu GY, Smolic M. Biomarkers for Assessing Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus on Sodium-Glucose Cotransporter 2 Inhibitor Therapy. J Clin Med 2023; 12:6561. [PMID: 37892698 PMCID: PMC10607797 DOI: 10.3390/jcm12206561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
In the current modern era of unhealthy lifestyles, non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and has become a serious global health problem. To date, there is no approved pharmacotherapy for the treatment of NAFLD, and necessary lifestyle changes such as weight loss, diet, and exercise are usually not sufficient to manage this disease. Patients with type 2 diabetes mellitus (T2DM) have a significantly higher risk of developing NAFLD and vice versa. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that have recently been approved for two other indications: chronic kidney disease and heart failure in diabetics and non-diabetics. They are also emerging as promising new agents for NAFLD treatment, as they have shown beneficial effects on hepatic inflammation, steatosis, and fibrosis. Studies in animals have reported favorable effects of SGLT2 inhibitors, and studies in patients also found positive effects on body mass index (BMI), insulin resistance, glucose levels, liver enzymes, apoptosis, and transcription factors. There are some theories regarding how SGLT2 inhibitors affect the liver, but the exact mechanism is not yet fully understood. Therefore, biomarkers to evaluate underlying mechanisms of action of SGLT2 inhibitors on the liver have now been scrutinized to assess their potential as a future in-label therapy for NAFLD. In addition, finding suitable non-invasive biomarkers could be helpful in clinical practice for the early detection of NAFLD in patients. This is crucial for a positive disease outcome. The aim of this review is to provide an overview of the most recent findings on the effects of SGLT2 inhibitors on NAFLD biomarkers and the potential of SGLT2 inhibitors to successfully treat NAFLD.
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Affiliation(s)
- Farah Khaznadar
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Omar Khaznadar
- Department of Radiology, “Dr. Juraj Njavro” National Memorial Hospital Vukovar, 32000 Vukovar, Croatia;
| | - Hrvoje Roguljic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
- Clinical Hospital Center, 31000 Osijek, Croatia
| | - Kristina Bojanic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
- Health Center Osijek-Baranja County, 31000 Osijek, Croatia
| | - Lucija Kuna Roguljic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Stjepan Siber
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Ines Bilic-Curcic
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
- Clinical Hospital Center, 31000 Osijek, Croatia
| | - George Y. Wu
- Department of Medicine, Division of Gastrenterology/Hepatology, University of Connecticut Health Center, Farmington, CT 06030, USA;
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
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12
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Zhai J, Wang Z, Zhang T, He L, Ma S, Zuo Q, Zhang G, Wang X, Guo Y. Canagliflozin and irbesartan ameliorate renal fibrosis via the TGF-β1/Smad signaling pathway in Dahl salt-sensitive rats. J Int Med Res 2023; 51:3000605231206289. [PMID: 37862678 PMCID: PMC10590049 DOI: 10.1177/03000605231206289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/21/2023] [Indexed: 10/22/2023] Open
Abstract
OBJECTIVES This study assessed the antifibrotic effects of canagliflozin, with or without irbesartan, on renal injury in Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. METHODS After the preconditioning stage, Dahl SS rats (n = 47) were divided into five experimental groups as follows: low-salt (LS, n = 7), HS (n = 10), HS with canagliflozin (n = 10), HS with irbesartan (n = 10), and HS with canagliflozin and irbesartan (n = 10). RESULTS The HS diet increased systolic blood pressure (SBP), renal fibrosis, fibrotic protein expression, and transforming growth factor-β1 (TGF-β1)/Smad2/3 pathway protein expression compared with the findings in the LS group. Irbesartan reduced SBP and slowed the loss of renal function. Canagliflozin significantly reduced body weight and renal fibrosis and suppressed the TGF-β1/Smad2/3 pathway. The combined therapy exerted better renoprotective effects on all outcome parameters. CONCLUSIONS These results indicate that canagliflozin and irbesartan exert different effects on renal injury in SS hypertensive rats, and the combined regimen could have stronger effects than either monotherapy.
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Affiliation(s)
- Jianlong Zhai
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Zhongli Wang
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Medical Examination Center, Hebei General Hospital, Shijiazhuang, China
| | - Tingting Zhang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Lili He
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Sai Ma
- Department of Pain Medicine, Hebei General Hospital, Shijiazhuang, China
| | - Qingjuan Zuo
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Guorui Zhang
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Cardiology, The Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, China
| | - Xinyu Wang
- Department of Internal Medicine, Hebei North University, Zhangjiakou, China
| | - Yifang Guo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
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13
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Zhao XY, Li SS, He YX, Yan LJ, Lv F, Liang QM, Gan YH, Han LP, Xu HD, Li YC, Qi YY. SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy. Ann Rheum Dis 2023; 82:1328-1340. [PMID: 37487609 DOI: 10.1136/ard-2023-224242] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/22/2023] [Indexed: 07/26/2023]
Abstract
OBJECTIVES The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. METHODS We applied empagliflozin treatment to lupus-prone MRL/lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. RESULTS In MRL/lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. CONCLUSION This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.
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Affiliation(s)
- Xin-Yu Zhao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
| | - Shuang-Shuang Li
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
- Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Ying-Xin He
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
- Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Jie Yan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
- Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Fu Lv
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
| | - Qi-Meng Liang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
| | - Yu-Hui Gan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
- Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Pei Han
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
| | - Hong-de Xu
- Zhengzhou University, Zhengzhou, Henan, China
- Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Yong-Chun Li
- Zhengzhou University, Zhengzhou, Henan, China
- Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuan-Yuan Qi
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Zhengzhou University, Zhengzhou, Henan, China
- Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Henan, China
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Heinrich NS, Pedersen RP, Vestergaard MB, Lindberg U, Andersen UB, Haddock B, Hansen TW, Fornoni A, Larsson HBW, Rossing P. Evaluation of the effects of ezetimibe on albuminuria and kidney fat in individuals with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2023; 25:2605-2615. [PMID: 37278273 DOI: 10.1111/dom.15146] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/08/2023] [Accepted: 05/12/2023] [Indexed: 06/07/2023]
Abstract
AIM To investigate the effects of ezetimibe on the urine albumin creatinine ratio (UACR) and kidney parenchyma fat content (kidney-PF) in individuals with type 2 diabetes (T2D) and early chronic kidney disease. MATERIALS AND METHODS A randomized, double-blind, placebo-controlled study of ezetimibe 10 mg once daily for 16 weeks in individuals with T2D and a UACR of 30 mg/g or higher was conducted. Kidney-PF was assessed with magnetic resonance spectroscopy. Geometric mean changes from baseline were derived from linear regressions. RESULTS A total of 49 participants were randomized to ezetimibe (n = 25) or placebo (n = 24). Overall, mean ± standard deviation age was 67 ± 7 years, body mass index was 31 ± 4 kg/m2 and the proportion of men was 84%. The mean estimated glomerular filtration rate was 76 ± 22 mL/min/1.73m2 and median (first-third quartile) UACR was 95 (41-297) mg/g. Median kidney-PF was 1.0% (0.3%-2.1%). Compared with placebo, ezetimibe did not significantly reduce UACR (mean [95% confidence interval] change: -3% [-28%-31%]) or kidney-PF (mean change: -38% [-66%-14%]). In participants with baseline kidney-PF above the median, ezetimibe reduced kidney-PF significantly (mean change: -60% [-84%--3%]) compared with placebo, while the reduction in UACR was not significant (mean change: -28% [-54%-15%]). CONCLUSIONS Ezetimibe did not reduce the UACR or kidney-PF on top of modern T2D management. However, kidney-PF was reduced with ezetimibe in participants with high baseline kidney-PF.
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Affiliation(s)
| | - Rune Ploegstra Pedersen
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet Glostrup, Glostrup, Denmark
| | - Mark Bitsch Vestergaard
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet Glostrup, Glostrup, Denmark
| | - Ulrich Lindberg
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet Glostrup, Glostrup, Denmark
| | - Ulrik Bjørn Andersen
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet Glostrup, Glostrup, Denmark
| | - Bryan Haddock
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet Glostrup, Glostrup, Denmark
| | | | - Alessia Fornoni
- Department of Medicine, Katz Family Division of Nephrology and Hypertension, University of Miami, Miami, Florida, USA
| | - Henrik Bo Wiberg Larsson
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet Glostrup, Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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15
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Shen Y, Cheng L, Xu M, Wang W, Wan Z, Xiong H, Guo W, Cai M, Xu F. SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis. Metabolism 2023:155657. [PMID: 37422021 DOI: 10.1016/j.metabol.2023.155657] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/30/2023] [Accepted: 07/05/2023] [Indexed: 07/10/2023]
Abstract
BACKGROUND AND RATIONALE Activation of hepatic stellate cells (HSCs), the central event of fibrosis, indicates the severe stage of non-alcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) participate in this process. Treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) alleviates liver fibrosis in patients with type 2 diabetes and NAFLD; however, the role of SGLT2i in ameliorating liver fibrosis in NAFLD by regulating miRNAs remains unclear. APPROACH AND RESULTS We monitored the expression of NAFLD-associated miRNAs in the livers of two NAFLD models and observed high expression of miR-34a-5p. miR-34a-5p was highly expressed in mouse primary liver non-parenchymal cells and LX-2 HSCs, and this miRNA was positively correlated with alanine transaminase levels in NAFLD models. Overexpression of miR-34a-5p enhanced LX-2 activation, whereas its inhibition prevented HSCs activation by regulating the TGFβ signaling pathway. The SGLT2i empagliflozin significantly downregulated miR-34a-5p, inhibited the TGFβ signaling pathway, and ameliorated hepatic fibrosis in NAFLD models. Subsequently, GREM2 was identified as a direct target of miR-34a-5p through database prediction and a dual-luciferase reporter assay. In LX-2 HSCs, the miR-34a-5p mimic and inhibitor directly downregulated and upregulated GREM2, respectively. Overexpressing GREM2 inactivated the TGFβ pathway whereas GREM2 knockdown activated it. Additionally, empagliflozin upregulated Grem2 expression in NAFLD models. In methionine- and choline-deficient diet-fed ob/ob mice, a fibrosis model, empagliflozin downregulated miR-34a-5p and upregulated Grem2 to improve liver fibrosis. CONCLUSIONS Empagliflozin ameliorates NAFLD-associated fibrosis by downregulating miR-34a-5p and targeting GREM2 to inhibit the TGFβ pathway in HSCs.
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Affiliation(s)
- Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Branch of National Clinical Research Center for Metabolic Diseases, Nanchang 330006, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Lidan Cheng
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Endocrinology and Metabolism, Jiujiang University Affiliated Hospital, Jiujiang 330300, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Wei Wang
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Gastroenterology, the First Affiliated Hospital of Yangtze University, Jingzhou 434000, China
| | - Zhiping Wan
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China; Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Haixia Xiong
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China; Branch of National Clinical Research Center for Metabolic Diseases, Nanchang 330006, China; Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Wanrong Guo
- Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Mengyin Cai
- Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China.
| | - Fen Xu
- Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China.
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16
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Saurin S, Meineck M, Rohr M, Roth W, Opatz T, Erkel G, Pautz A, Weinmann-Menke J. The macrocyclic lactone oxacyclododecindione reduces fibrosis progression. Front Pharmacol 2023; 14:1200164. [PMID: 37383717 PMCID: PMC10294233 DOI: 10.3389/fphar.2023.1200164] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/23/2023] [Indexed: 06/30/2023] Open
Abstract
Background: Renal fibrosis is one of the most important triggers of chronic kidney disease (CKD), and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation, and extracellular matrix (ECM) deposition, a drug that can address all these processes might be an interesting therapeutic option. Methods: We tested in vivo in an ischemia-reperfusion (I/R) model in C57BL/6 mice and in kidney tubular epithelial cells (TEC) (HK2 cell line and primary cells) whether the natural product oxacyclododecindione (Oxa) reduces fibrosis progression in kidney disease. This was evaluated by Western blot, mRNA expression, and mass spectrometry secretome analyses, as well as by immunohistochemistry. Results: Indeed, Oxa blocked the expression of epithelial-mesenchymal transition marker proteins and reduced renal damage, immune cell infiltration, and collagen expression and deposition, both in vivo and in vitro. Remarkably, the beneficial effects of Oxa were also detected when the natural product was administered at a time point of established fibrotic changes, a situation close to the clinical situation. Initial in vitro experiments demonstrated that a synthetic Oxa derivative possesses similar features. Conclusion: Although open questions such as possible side effects need to be investigated, our results indicate that the combination of anti-inflammatory and anti-fibrotic effects of Oxa make the substance a promising candidate for a new therapeutic approach in fibrosis treatment, and thus in the prevention of kidney disease progression.
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Affiliation(s)
- Sabrina Saurin
- Department of Nephrology, Center of Immunotherapy, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Myriam Meineck
- Department of Nephrology, Center of Immunotherapy, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Markus Rohr
- Department of Molecular Biotechnology and Systems Biology, RPTU Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Wilfried Roth
- Institute of Pathology, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Till Opatz
- Department of Chemistry, Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Gerhard Erkel
- Department of Molecular Biotechnology and Systems Biology, RPTU Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Andrea Pautz
- Institute of Pharmacology, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Julia Weinmann-Menke
- Department of Nephrology, Center of Immunotherapy, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
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17
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Ren L, Cui H, Wang Y, Ju F, Cai Y, Gang X, Wang G. The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects. Biomed Pharmacother 2023; 161:114465. [PMID: 36870280 DOI: 10.1016/j.biopha.2023.114465] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/20/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Lipotoxicity is the dysregulation of the lipid environment and/or intracellular composition that leads to accumulation of harmful lipids and ultimately to organelle dysfunction, abnormal activation of intracellular signaling pathways, chronic inflammation and cell death. It plays an important role in the development of acute kidney injury and chronic kidney disease, including diabetic nephropathy, obesity-related glomerulopathy, age-related kidney disease, polycystic kidney disease, and the like. However, the mechanisms of lipid overload and kidney injury remain poorly understood. Herein, we discuss two pivotal aspects of lipotoxic kidney injury. First, we analyzed the mechanism of lipid accumulation in the kidney. Accumulating data indicate that the mechanisms of lipid overload in different kidney diseases are inconsistent. Second, we summarize the multiple mechanisms by which lipotoxic species affect the kidney cell behavior, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, dysregulated autophagy, and inflammation, highlighting the central role of oxidative stress. Blocking the molecular pathways of lipid accumulation in the kidney and the damage of the kidney by lipid overload may be potential therapeutic targets for kidney disease, and antioxidant drugs may play a pivotal role in the treatment of kidney disease in the future.
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Affiliation(s)
- Linan Ren
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China; Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Haiying Cui
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China; Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Yao Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Feng Ju
- Department of Orthopedics, Yuci District People's Hospital, Yuci 030600, Shanxi, China
| | - Yunjia Cai
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China.
| | - Guixia Wang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China.
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18
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Baek J, Sas K, He C, Nair V, Giblin W, Inoki A, Zhang H, Yingbao Y, Hodgin J, Nelson RG, Brosius FC, Kretzler M, Stemmer PM, Lombard DB, Pennathur S. The deacylase sirtuin 5 reduces malonylation in nonmitochondrial metabolic pathways in diabetic kidney disease. J Biol Chem 2023; 299:102960. [PMID: 36736426 PMCID: PMC9996370 DOI: 10.1016/j.jbc.2023.102960] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 02/05/2023] Open
Abstract
Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. We performed a proteomics analysis of malonylated peptides and found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in nonmitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation. To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians, which revealed a tubulointerstitial-specific increase in Sirt5 expression. These data were further corroborated by immunofluorescence data of SIRT5 from nondiabetic and DKD cohorts. Furthermore, overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis. Conversely, we observed reduced glycolysis with decreased SIRT5 expression. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Taken together, our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.
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Affiliation(s)
- Judy Baek
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Kelli Sas
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Chenchen He
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Viji Nair
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - William Giblin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ayaka Inoki
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hongyu Zhang
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Yang Yingbao
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeffrey Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Robert G Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA
| | - Frank C Brosius
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA; Department of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Matthias Kretzler
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Paul M Stemmer
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA
| | - David B Lombard
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA; Institute of Gerontology, University of Michigan, Ann Arbor, Michigan, USA
| | - Subramaniam Pennathur
- Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
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19
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Sun X, Wang G. Renal outcomes with sodium-glucose cotransporters 2 inhibitors. Front Endocrinol (Lausanne) 2022; 13:1063341. [PMID: 36531469 PMCID: PMC9752889 DOI: 10.3389/fendo.2022.1063341] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/08/2022] [Indexed: 12/05/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most serious complications of diabetes. Therefore, delaying and preventing the progression of DN becomes an important goal in the clinical treatment of type 2 diabetes mellitus. Recent studies confirm that sodium-glucose cotransporters 2 inhibitors (SGLT2is) have been regarded as effective glucose-lowering drugs with renal protective effect. In this review, we summarize in detail the present knowledge of the effects of SGLT2is on renal outcomes by analyzing the experimental data in preclinical study, the effects of SGLT2is on estimated glomerular flitration rates (eGFRs) and urinary albumin-creatinine ratios (UACRs) from clinical trials and observational studies, and renal events (such as renal death or renal failure requiring renal replacement therapy) in some large prospective cardiovaslucar outcomes trials. The underlying mechanisms for renoprotective activity of SGLT2is have been demondtrated in multiple diabetic and nondiabetic animal models including kidney-specific effects and secondary kidney effects related to amelioration in blood glucose and blood pressure. In conclusion, these promising results show that SGLT2is act beneficially in terms of the kidney for diabetic patients.
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Affiliation(s)
| | - Guohong Wang
- Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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20
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The Contribution of Lipotoxicity to Diabetic Kidney Disease. Cells 2022; 11:cells11203236. [PMID: 36291104 PMCID: PMC9601125 DOI: 10.3390/cells11203236] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/02/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
Lipotoxicity is a fundamental pathophysiologic mechanism in diabetes and non-alcoholic fatty liver disease and is now increasingly recognized in diabetic kidney disease (DKD) pathogenesis. This review highlights lipotoxicity pathways in the podocyte and proximal tubule cell, which are arguably the two most critical sites in the nephron for DKD. The discussion focuses on membrane transporters and lipid droplets, which represent potential therapeutic targets, as well as current and developing pharmacologic approaches to reduce renal lipotoxicity.
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21
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Suplotovа LA, Kulmametova DS, Fedorova AI, Dushina TS, Makarova OB. Effect of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2022:83-89. [DOI: 10.21518/2079-701x-2022-16-15-83-89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Non-alcoholic fatty liver disease is one of the most common liver diseases, morphologically representing a whole spectrum of pathological conditions, from steatosis and steatohepatitis to fibrosis, the clinical outcomes of which can be liver cirrhosis and hepatocellular carcinoma. The frequency of adverse outcomes in the course of non-alcoholic fatty liver disease significantly increases against the background of type 2 diabetes mellitus, which is probably due to the pathogenetic synergy of non-alcoholic fatty liver disease and type 2 diabetes mellitus associated with metabolic syndrome. The commonality of pathogenetic links, as a result, suggests the unidirectionality of therapeutic approaches. In this connection, a search was made for studies and meta-analyses in large electronic databases (MEDLINE, Scopus, UpToDate, CyberLeninka) in order to study modern methods of pharmacotherapy for non-alcoholic fatty liver disease and type 2 diabetes mellitus. The results of a number of experimental and clinical studies evaluating the effect of hypoglycemic drugs of the group of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease demonstrate a wide range of intrahepatic effects that affect the manifestations of liver steatosis and fibrosis through the regulation of oxidative stress, endoplasmic reticulum stress, effects on intrahepatic inflammation, autophagy and apoptosis, as well as indirectly affecting hepatic metabolism, by reducing body weight. In addition, today gliflozins are rushing to occupy a completely new therapeutic niche, demonstrating anticarcinogenic effects in experimental studies. Thus, the pleiotropic effect of inhibitors of the sodium-glucose cotransporter type 2 suggests a potential hepatoprotective effect in the treatment of non-alcoholic fatty liver disease and its outcomes.
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22
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Lin K, Yang N, Luo W, Qian JF, Zhu WW, Ye SJ, Yuan CX, Xu DY, Liang G, Huang WJ, Shan PR. Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling. Acta Pharmacol Sin 2022; 43:2624-2635. [PMID: 35217813 PMCID: PMC9525284 DOI: 10.1038/s41401-022-00885-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 02/06/2022] [Indexed: 12/22/2022]
Abstract
Obesity is an important independent risk factor for cardiovascular diseases, remaining an important health concern worldwide. Evidence shows that saturated fatty acid-induced inflammation in cardiomyocytes contributes to obesity-related cardiomyopathy. Dapagliflozin (Dapa), a selective SGLT2 inhibitor, exerts a favorable preventive activity in heart failure. In this study, we investigated the protective effect of Dapa against cardiomyopathy caused by high fat diet-induced obesity in vitro and in vivo. Cultured rat cardiomyocyte H9c2 cells were pretreated with Dapa (1, 2.5 μM) for 1.5 h, followed by treatment with palmitic acid (PA, 200 μM) for 24 h. We showed that Dapa pretreatment concentration-dependently attenuated PA-induced cell hypertrophy, fibrosis and apoptosis. Transcriptome analysis revealed that inhibition of PA-activated MAPK/AP-1 pathway contributed to the protective effect of Dapa in H9c2 cells, and this was confirmed by anti-p-cJUN fluorescence staining assay. Using surface plasmon resonance analysis we found the direct binding of Dapa with NHE1. Gain and loss of function experiments further demonstrated the role of NHE1 in the protection of Dapa. In vivo experiments were conducted in mice fed a high fat diet for 5 months. The mice were administered Dapa (1 mg·kg-1·d-1, i.g.) in the last 2 months. Dapa administration significantly reduced the body weight and improved the serum lipid profiles. Dapa administration also alleviated HFD-induced cardiac dysfunction and cardiac aberrant remodeling via inhibiting MAPK/AP-1 pathway and ameliorating cardiac inflammation. In conclusion, Dapa exerts a direct protective effect against saturated fatty acid-induced cardiomyocyte injury in addition to the lowering effect on serum lipids. The protective effect results from negative regulating MAPK/AP-1 pathway in a NHE1-dependent way. The current study highlights the potential of clinical use of Dapa in the prevention of obesity-related cardiac dysfunction.
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Affiliation(s)
- Ke Lin
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Na Yang
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Jin-Fu Qian
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Wei-Wei Zhu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Shi-Ju Ye
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
| | - Chen-Xin Yuan
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
| | - Di-Yun Xu
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Wei-Jian Huang
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
| | - Pei-Ren Shan
- Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
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23
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SGLT2 inhibitors attenuate nephrin loss and enhance TGF-β 1 secretion in type 2 diabetes patients with albuminuria: a randomized clinical trial. Sci Rep 2022; 12:15695. [PMID: 36127497 PMCID: PMC9489863 DOI: 10.1038/s41598-022-19988-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 09/07/2022] [Indexed: 11/15/2022] Open
Abstract
To evaluate the effect of SGLT2 inhibitor (SGLT2i) on albuminuria, nephrin (NPH) and transforming-growth-factor-beta1 (TGF-β1) levels in urine and low-grade inflammation in type 2 diabetes (T2D) patients. A randomized, blank-controlled clinical trial included 68 T2D patients and 10 controls. Based on the urinary albumin-to-creatinine ratio (UACR), 68 diabetic patients were stratified into three levels, UACR < 30 mg/g, UACR ≧ 30 mg/g to ≦ 300 mg/g and UACR ˃ 300 mg/g, who were randomized (1:1:1) to receive SGLT2i treatment for 12 weeks. The concentrations of NPH and TGF-β1 in urine were measured as indications of podocyte injury and renal fibrosis. Low-grade inflammation was assessed by the levels of IL-6, TNFα and hsCRP. After 12 weeks of SGLT2i treatment, the levels of UACR and NPH decreased, UTGF-β1 increased in the T2D with microalbuminuria and macroalbuminuria groups, NPH (1.12 [0.59, 1.29] vs. 0.71 [0.41, 1.07] µg/ml, P = 0.022) and (1.29 [0.99, 1.96] vs. 0.93 [0.57, 1.31] µg/ml, P = 0.002), UTGF-β1 (4.88 ± 1.31 vs. 7.27 ± 1.21 pg/ml, P < 0.001) and (4.30 ± 1.34 vs. 6.78 ± 2.59 pg/ml, P < 0.001), respectively. The changes in NPH were positively correlated with the UACR and negatively correlated with UTGF-β1 in T2D with albuminuria. SGLT2i alleviate nephrin loss and enhance TGF-β1 excretion in urine in T2DM with albuminuria. The anti-albuminuric effect of SGLT2i could be attributed to mitigating podocyte apoptosis and attenuating renal fibrosis. Trial registration This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.
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24
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Renoprotective effects of dapagliflozin in an iron overload non-diabetic rat model. Adv Med Sci 2022; 67:311-315. [PMID: 36037575 DOI: 10.1016/j.advms.2022.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/30/2022] [Accepted: 08/16/2022] [Indexed: 11/22/2022]
Abstract
PURPOSE Sodium glucose co-transporter (SGLT) 2 inhibitors are oral anti-diabetic drugs with proven kidney protective effects. Renal protective effects in non-diabetic individuals have also been shown in recent studies. The aim of this study was to determine the renal protective effects of dapagliflozin by evaluating the oxidative stress markers in the kidney tissue and demonstrating it in renal histological sections in an iron-overloaded rat model. METHODS A total of 24 Wistar Albino rats were separated into 3 groups of 8 rats. Iron sucrose (60 mg/kg/day) was administered intraperitoneally to the first group (Group Fe) (n = 8), iron sucrose and dapagliflozin (0.1 mg/kg/day) to the second group (Group Fe + D) (n = 8) and intraperitoneal saline as placebo to the control group (Group C) (n = 8) for 4 weeks. The glomerular changes were semi-quantitatively scored with Oxford Classification. Oxidative stress was analyzed from the tissue fluorescent oxidation product (FLOP), malondialdehyde (MDA) and total sulfhydryl (T-SH) levels. RESULTS Dapagliflozin prevented glomerular and mesangial damage of iron overload in the non-diabetic rat model. MDA levels were significantly higher in Group Fe compared to the Group C, and there was no significant difference between the Fe + D group and Group C. T-SH levels were preserved in the Fe + D group and were significantly higher than in the Fe group. CONCLUSIONS The results of this study showed that dapagliflozin helped preserve the glomerular and mesangial structure histologically and reduced oxidative stress markers in a non-diabetic iron overload rat model.
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25
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Czernuszewicz TJ, Aji AM, Moore CJ, Montgomery SA, Velasco B, Torres G, Anand KS, Johnson KA, Deal AM, Zukić D, McCormick M, Schnabl B, Gallippi CM, Dayton PA, Gessner RC. Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models. Hepatol Commun 2022; 6:1827-1839. [PMID: 35202510 PMCID: PMC9234684 DOI: 10.1002/hep4.1912] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Shear wave elastography (SWE) is an ultrasound-based stiffness quantification technology that is used for noninvasive liver fibrosis assessment. However, despite widescale clinical adoption, SWE is largely unused by preclinical researchers and drug developers for studies of liver disease progression in small animal models due to significant experimental, technical, and reproducibility challenges. Therefore, the aim of this work was to develop a tool designed specifically for assessing liver stiffness and echogenicity in small animals to better enable longitudinal preclinical studies. A high-frequency linear array transducer (12-24 MHz) was integrated into a robotic small animal ultrasound system (Vega; SonoVol, Inc., Durham, NC) to perform liver stiffness and echogenicity measurements in three dimensions. The instrument was validated with tissue-mimicking phantoms and a mouse model of nonalcoholic steatohepatitis. Female C57BL/6J mice (n = 40) were placed on choline-deficient, L-amino acid-defined, high-fat diet and imaged longitudinally for 15 weeks. A subset was sacrificed after each imaging timepoint (n = 5) for histological validation, and analyses of receiver operating characteristic (ROC) curves were performed. Results demonstrated that robotic measurements of echogenicity and stiffness were most strongly correlated with macrovesicular steatosis (R2 = 0.891) and fibrosis (R2 = 0.839), respectively. For diagnostic classification of fibrosis (Ishak score), areas under ROC (AUROCs) curves were 0.969 for ≥Ishak1, 0.984 for ≥Ishak2, 0.980 for ≥Ishak3, and 0.969 for ≥Ishak4. For classification of macrovesicular steatosis (S-score), AUROCs were 1.00 for ≥S2 and 0.997 for ≥S3. Average scanning and analysis time was <5 minutes/liver. Conclusion: Robotic SWE in small animals is feasible and sensitive to small changes in liver disease state, facilitating in vivo staging of rodent liver disease with minimal sonographic expertise.
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Affiliation(s)
- Tomasz J Czernuszewicz
- SonoVol, Inc.DurhamNCUSA.,Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | | | | | - Stephanie A Montgomery
- Department of Pathology and Laboratory MedicineUniversity of North CarolinaChapel HillNCUSA
| | - Brian Velasco
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Gabriela Torres
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Keerthi S Anand
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Kennita A Johnson
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Allison M Deal
- Biostatistics CoreLineberger Cancer CenterUniversity of North CarolinaChapel HillNCUSA
| | | | | | - Bernd Schnabl
- 19979Department of MedicineUniversity of California San DiegoLa JollaCAUSA.,19979Department of MedicineVA San Diego Healthcare SystemSan DiegoCAUSA
| | - Caterina M Gallippi
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
| | - Paul A Dayton
- Joint Department of Biomedical EngineeringUniversity of North Carolina and North Carolina State UniversityChapel HillNCUSA
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26
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Li N, Zhou H. Sodium-glucose Cotransporter Type 2 Inhibitors: A New Insight into the Molecular Mechanisms of Diabetic Nephropathy. Curr Pharm Des 2022; 28:2131-2139. [PMID: 35718973 DOI: 10.2174/1381612828666220617153331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 03/15/2022] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy is one of the chronic microvascular complications of diabetes and is a leading cause of end-stage renal disease. Fortunately, clinical trials have demonstrated that sodium-glucose cotransporter type 2 inhibitors could decrease proteinuria and improve renal endpoints and are promising agents for the treatment of diabetic nephropathy. The renoprotective effects of sodium-glucose cotransporter type 2 inhibitors cannot be simply attributed to their advantages in aspects of metabolic benefits, such as glycemic control, lowering blood pressure, and control of serum uric acid, or improving hemodynamics associated with decreased glomerular filtration pressure. Some preclinical evidence suggests that sodium-glucose cotransporter type 2 inhibitors exert their renoprotective effects by multiple mechanisms, including attenuation of oxidative and endoplasmic reticulum stresses, anti-fibrosis and anti-inflammation, protection of podocytes, suppression of megalin function, improvement of renal hypoxia, restored mitochondrial dysfunction and autophagy, as well as inhibition of sodium-hydrogen exchanger 3. In the present study, the detailed molecular mechanisms of sodium-glucose cotransporter type 2 inhibitors with the actions of diabetic nephropathy were reviewed, with the purpose of providing the basis for drug selection for the treatment of diabetic nephropathy.
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Affiliation(s)
- Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice. Int J Mol Sci 2022; 23:ijms23105675. [PMID: 35628485 PMCID: PMC9147974 DOI: 10.3390/ijms23105675] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022] Open
Abstract
Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of "healthy adipose expansion". Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.
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Bellido V, Martínez J, Calvo F, Villarroel A, Lecumberri E, Moreno J, Morillas C, Rodrigo S, Izarra A, Lecube A. Beyond the Glycaemic Control of Dapagliflozin: Microangiopathy and Non-classical Complications. Diabetes Ther 2022; 13:873-888. [PMID: 35338446 PMCID: PMC9076778 DOI: 10.1007/s13300-022-01237-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/21/2022] [Indexed: 11/23/2022] Open
Abstract
Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure (HF) with reduced ejection fraction (EF) and chronic kidney disease (CKD). In monotherapy or as an additive therapy, dapagliflozin aids glycaemic control, is associated with reductions in blood pressure and weight, and promotes a favourable lipid profile. In this review, we address the impact of dapagliflozin on cardiovascular risk factors and common microangiopathic complications such as kidney disease and retinopathy in patients with T2DM. Furthermore, we evaluate its potential beneficial effects on other less frequent complications of diabetes, such as macular oedema, cognitive impairment, non-alcoholic fatty liver disease and respiratory disorders during sleep. Moreover, the underuse of SGLT2i in clinical practice is discussed. Our goal is to help translate this evidence into clinical practice.
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Affiliation(s)
- Virginia Bellido
- Endocrinology and Nutrition Department, Virgen del Rocío University Hospital, Sevilla, Spain
| | | | - Fernando Calvo
- Endocrinology and Nutrition Department, "Lozano Blesa" Clinical Hospital, Zaragoza, Spain
| | | | - Edurne Lecumberri
- Endocrinology and Nutrition Department, Ramón y Cajal University Hospital, Madrid, Spain
| | - Juan Moreno
- Medical Department, AstraZeneca Spain, Madrid, Spain
| | - Carlos Morillas
- Endocrinology and Nutrition Department, Dr Peset University Hospital of Valencia, Valencia, Spain
| | | | | | - Albert Lecube
- Research Group On Obesity, Diabetes and Metabolism (ODIM), Institute of Biomedical Research of Lleida (IRBLleida), Endocrinology and Nutrition Department, Arnau de Vilanova University Hospital, Lleida, University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain.
- Biomedical Research Networking Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Carlos III Health Institute, Madrid, Spain.
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Durcan E, Ozkan S, Saygi HI, Dincer MT, Korkmaz OP, Sahin S, Karaca C, Sulu C, Bakir A, Ozkaya HM, Trabulus S, Guzel E, Seyahi N, Gonen MS. Effects of SGLT2 inhibitors on patients with diabetic kidney disease: A preliminary study on the basis of podocyturia. J Diabetes 2022; 14:236-246. [PMID: 35229458 PMCID: PMC9060072 DOI: 10.1111/1753-0407.13261] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/27/2022] [Accepted: 02/13/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the glomerulus through the evaluation of podocyturia in patients with diabetic kidney disease (DKD). METHODS The study population was composed of 40 male patients with type 2 diabetes mellitus; 22 of them received SGLT2i (SGLT2i group), and the others who did not were the control. The DKD-related parameters of patients were monitored before SGLT2i initiation, and then in the third and sixth month of the follow-up period. Patients' demographic, clinical, laboratory, and follow-up data were obtained from medical charts. Microalbuminuria was measured in 24-h urine. The number of podocytes in the urine was determined by immunocytochemical staining of two different markers, namely podocalyxin (podx) and synaptopodin (synpo). Concentrations of urine stromal cell-derived factor 1a and vascular endothelial growth factor cytokines were quantified with an enzyme-linked immunosorbent assay kit. RESULTS At the end of the follow-up period, decreases in glycosylated hemoglobin, glucose, systolic and diastolic blood pressure, uric acid level, and microalbuminuria, and improvement in body mass index level and weight loss were significant for the SGLT2i group. On the other hand, there was no significant difference in terms of these parameters in the control group. The excretion of synaptopodin-positive (synpo+ ) and podocalyxin-positive (podx+ ) cells was significantly reduced at the end of the follow-up period for the SGLT2i group, while there was no significant change for the control. CONCLUSIONS At the end of the follow-up period, male patients receiving SGLT2i had better DKD-related parameters and podocyturia levels compared to baseline and the control group. Our data support the notion that SGLT2i might have structural benefits for glomerular health.
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Affiliation(s)
- Emre Durcan
- Division of Endocrinology and Metabolism, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Serbay Ozkan
- Department of Histology and EmbryologyCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Halil Ibrahim Saygi
- Department of Histology and EmbryologyCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Mevlut Tamer Dincer
- Division of Nephrology, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Ozge Polat Korkmaz
- Division of Endocrinology and Metabolism, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Serdar Sahin
- Division of Endocrinology and Metabolism, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Cebrail Karaca
- Division of Nephrology, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Cem Sulu
- Division of Endocrinology and Metabolism, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Alev Bakir
- Department of Biostatistics and Medical InformaticsHalic UniversityIstanbulTurkey
| | - Hande Mefkure Ozkaya
- Division of Endocrinology and Metabolism, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Sinan Trabulus
- Division of Nephrology, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Elif Guzel
- Department of Histology and EmbryologyCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Nurhan Seyahi
- Division of Nephrology, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
| | - Mustafa Sait Gonen
- Division of Endocrinology and Metabolism, Department of Internal MedicineCerrahpasa Medical School, Istanbul University‐CerrahpasaIstanbulTurkey
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Anti-Diabetic Effects of Ethanol Extract from Sanghuangporous vaninii in High-Fat/Sucrose Diet and Streptozotocin-Induced Diabetic Mice by Modulating Gut Microbiota. Foods 2022; 11:foods11070974. [PMID: 35407061 PMCID: PMC8997417 DOI: 10.3390/foods11070974] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 01/27/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) may lead to abnormally elevated blood glucose, lipid metabolism disorder, and low-grade inflammation. Besides, the development of T2DM is always accompanied by gut microbiota dysbiosis and metabolic dysfunction. In this study, the T2DM mice model was established by feeding a high-fat/sucrose diet combined with injecting a low dose of streptozotocin. Additionally, the effects of oral administration of ethanol extract from Sanghuangporous vaninii (SVE) on T2DM and its complications (including hypoglycemia, hyperlipidemia, inflammation, and gut microbiota dysbiosis) were investigated. The results showed SVE could improve body weight, glycolipid metabolism, and inflammation-related parameters. Besides, SVE intervention effectively ameliorated the diabetes-induced pancreas and jejunum injury. Furthermore, SVE intervention significantly increased the relative abundances of Akkermansia, Dubosiella, Bacteroides, and Parabacteroides, and decreased the levels of Lactobacillus, Flavonifractor, Odoribacter, and Desulfovibrio compared to the model group (LDA > 3.0, p < 0.05). Metabolic function prediction of the intestinal microbiota by PICRUSt revealed that glycerolipid metabolism, insulin signaling pathway, PI3K-Akt signaling pathway, and fatty acid degradation were enriched in the diabetic mice treated with SVE. Moreover, the integrative analysis indicated that the key intestinal microbial phylotypes in response to SVE intervention were strongly correlated with glucose and lipid metabolism-associated biochemical parameters. These findings demonstrated that SVE has the potential to alleviate T2DM and its complications by modulating the gut microbiota imbalance.
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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Reverte V, Rodriguez F, Oltra L, Moreno JM, Llinas MT, Shea CM, Schwartzkopf CD, Buys ES, Masferrer JL, Salazar FJ. SGLT2 inhibition potentiates the cardiovascular, renal and metabolic effects of sGC stimulation in hypertensive rats with prolonged exposure to high fat diet. Am J Physiol Heart Circ Physiol 2022; 322:H523-H536. [PMID: 35119333 PMCID: PMC8917931 DOI: 10.1152/ajpheart.00386.2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Prolonged high-fat diet (HFD) accelerates the cardiovascular, renal, and metabolic dysfunction in hypertensive rats with altered renal development (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and metabolic function in settings of hypertension and obesity. This study examined whether 6 wk treatment with an SGLT2 inhibitor (empagliflozin, 7 mg/kg/day) enhances the cardiovascular, renal, and metabolic effects of a sGC stimulator (praliciguat, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat abdominal volume (FAV), insulin resistance, leptin and triglycerides levels, and intrarenal infiltration of inflammatory cells were higher, but cardiac output and creatinine clearance were lower in hypertensive rats (n = 15) than in normotensive rats (n = 7). Praliciguat administration (n = 10) to hypertensive rats reduced (P < 0.05) AP, FAV, plasma concentrations of leptin and triglycerides, and increased (P < 0.05) cardiac output and creatinine clearance. Empagliflozin administration (n = 8) only increased (P < 0.05) glucosuria and creatinine clearance and decreased (P < 0.05) plasma leptin and triglycerides concentrations in hypertensive rats. Simultaneous administration of praliciguat and empagliflozin (n = 10) accelerated the decrease in AP, improved glucose tolerance, reduced (P < 0.05) incremental body weight gain, and decreased (P < 0.05) insulin resistance index, RVR, and the infiltration of T-CD3 lymphocytes in renal cortex and renal medulla. In summary, the combined administration of praliciguat and empagliflozin leads to a greater improvement of the cardiovascular, renal, and metabolic dysfunction secondary to prolonged exposure to HFD in hypertensive rats with ARDev than the treatment with either praliciguat or empagliflozin alone. NEW & NOTEWORTHY This is the first study, to our knowledge, showing that SGLT2 inhibition potentiates the beneficial cardiovascular, renal, and metabolic effects elicited by sGC stimulation in hypertensive rats with prolonged high-fat diet. The effects of the simultaneous administration of praliciguat and empagliflozin are greater than those elicited by either one alone. The effects of the simultaneous treatment may be related to a greater reduction in the inflammatory status.
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Affiliation(s)
- Virginia Reverte
- Department of Physiology, School of Medicine, CEIR Mare Nostrum University of Murcia, Murcia, Spain.,Biomedical Research Institute, Murcia, Spain
| | - Francisca Rodriguez
- Department of Physiology, School of Medicine, CEIR Mare Nostrum University of Murcia, Murcia, Spain.,Biomedical Research Institute, Murcia, Spain
| | - Lidia Oltra
- Biomedical Research Institute, Murcia, Spain
| | - Juan M Moreno
- Department of Physiology, School of Medicine, CEIR Mare Nostrum University of Murcia, Murcia, Spain.,Biomedical Research Institute, Murcia, Spain
| | - Maria T Llinas
- Department of Physiology, School of Medicine, CEIR Mare Nostrum University of Murcia, Murcia, Spain.,Biomedical Research Institute, Murcia, Spain
| | - Courtney M Shea
- Cyclerion Therapeutics, Cambridge, Massachusetts, United States
| | | | - Emmanuel S Buys
- Cyclerion Therapeutics, Cambridge, Massachusetts, United States
| | | | - F Javier Salazar
- Department of Physiology, School of Medicine, CEIR Mare Nostrum University of Murcia, Murcia, Spain.,Biomedical Research Institute, Murcia, Spain
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Abstract
Sodium glucose cotransporter 2 (SGLT-2) inhibitors are the latest class of antidiabetic medications. They prevent glucose reabsorption in the proximal convoluted tubule to decrease blood sugar. Several animal studies revealed that SGLT-2 is profoundly involved in the inflammatory response, fibrogenesis, and regulation of numerous intracellular signaling pathways. Likewise, SGLT-2 inhibitors markedly attenuated inflammation and fibrogenesis and improved the function of damaged organ in animal studies, observational studies, and clinical trials. SGLT-2 inhibitors can decrease blood pressure and ameliorate hypertriglyceridemia and obesity. Likewise, they improve the outcome of cardiovascular diseases such as heart failure, arrhythmias, and ischemic heart disease. SGLT-2 inhibitors are associated with lower cardiovascular and all-cause mortality as well. Meanwhile, they protect against nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, acute kidney injury, and improve micro- and macroalbuminuria. SGLT-2 inhibitors can reprogram numerous signaling pathways to improve NAFLD, cardiovascular diseases, and renal diseases. For instance, they enhance lipolysis, ketogenesis, mitochondrial biogenesis, and autophagy while they attenuate the renin-angiotensin-aldosterone system, lipogenesis, endoplasmic reticulum stress, oxidative stress, apoptosis, and fibrogenesis. This review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases and dissects the underlying molecular mechanisms in detail. This narrative review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases using the results of latest observational studies, clinical trials, and meta-analyses. Thereafter, it dissects the underlying molecular mechanisms involved in the clinical effects of SGLT-2 inhibitors on these diseases.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice. Int J Mol Sci 2021; 22:ijms222212408. [PMID: 34830289 PMCID: PMC8621539 DOI: 10.3390/ijms222212408] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/15/2021] [Accepted: 11/15/2021] [Indexed: 01/10/2023] Open
Abstract
High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.
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Sun Y, Cui S, Hou Y, Yi F. The Updates of Podocyte Lipid Metabolism in Proteinuric Kidney Disease. KIDNEY DISEASES (BASEL, SWITZERLAND) 2021; 7:438-451. [PMID: 34901191 DOI: 10.1159/000518132] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/24/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Podocytes, functionally specialized and terminally differentiated glomerular visceral epithelial cells, are critical for maintaining the structure and function of the glomerular filtration barrier. Podocyte injury is considered as the most important early event contributing to proteinuric kidney diseases such as obesity-related renal disease, diabetic kidney disease, focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Although considerable advances have been made in the understanding of mechanisms that trigger podocyte injury, cell-specific and effective treatments are not clinically available. SUMMARY Emerging evidence has indicated that the disorder of podocyte lipid metabolism is closely associated with various proteinuric kidney diseases. Excessive lipid accumulation in podocytes leads to cellular dysfunction which is defined as lipotoxicity, a phenomenon characterized by mitochondrial oxidative stress, actin cytoskeleton remodeling, insulin resistance, and inflammatory response that can eventually result in podocyte hypertrophy, detachment, and death. In this review, we summarize recent advances in the understanding of lipids in podocyte biological function and the regulatory mechanisms leading to podocyte lipid accumulation in proteinuric kidney disease. KEY MESSAGES Targeting podocyte lipid metabolism may represent a novel therapeutic strategy for patients with proteinuric kidney disease.
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Affiliation(s)
- Yu Sun
- The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Sijia Cui
- The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yunfeng Hou
- Intensive Care Unit, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Fan Yi
- The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
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Abstract
Obesity-related glomerulopathy (ORG) and other obesity-associated kidney diseases pose a major challenge to the treating nephrologist. We review the benefits of weight loss and optimal management of ORG and kidney disease in the setting of obesity. Therapeutic strategies in ORG were limited mainly in the past to weight loss through lifestyle interventions and bariatric surgery, antihypertensive treatment, and renin-angiotensin-aldosterone system blockade. Current approaches to obtain the desired weight loss include novel pharmacologic therapies that have been approved for the treatment of diabetes while offering kidney protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1-receptor agonists. This review focuses on the nephroprotective role of the renin-angiotensin-aldosterone system blockade and of these new pharmacologic agents, and on the renal effects of bariatric surgery in chronic kidney disease.
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Affiliation(s)
- Michal Herman-Edelstein
- Nephrology Department, Rabin Medical Center, Petach Tikva, Israel; Nephrology Research Laboratory, Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
| | - Talia Weinstein
- Department of Nephrology and Hypertension, Tel Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
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Coelho FDS, Borges-Canha M, von Hafe M, Neves JS, Vale C, Leite AR, Carvalho D, Leite-Moreira A. Effects of sodium-glucose co-transporter 2 inhibitors on liver parameters and steatosis: A meta-analysis of randomized clinical trials. Diabetes Metab Res Rev 2021; 37:e3413. [PMID: 33010191 DOI: 10.1002/dmrr.3413] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/12/2020] [Accepted: 08/23/2020] [Indexed: 12/17/2022]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in Western countries and a common comorbidity with type 2 diabetes (T2D). It lacks effective pharmacotherapy. We aimed to summarize the evidence on the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on liver structure and function. MATERIALS AND METHODS Meta-analysis of randomized clinical trials in PubMed, Web of Science and ClinicalTrials.gov from their inception to April 2019. Trials evaluating liver function and/or structure and comparing SGLT2 inhibitors with placebo or other oral antidiabetic drugs in patients with T2D were included. Twenty studies (from 3033) were included. A total of 1950 patients with T2D, with or without NAFLD, were treated with SGLT2 inhibitors for at least 8 weeks, and 1900 patients were used as controls. Independent extraction was carried out by two observers. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis. RESULTS SGLT2 inhibitors induced a significant decrease in serum alanine (-7.43U/L, [95%CI -12.14, -2.71], p < 0.01), in aspartate aminotransferases (-2.83U/L, [-4.71, -0.95], p < 0.01), as well as in gamma glutamyl transferase (-8.21U/L, [-9.52, -6.91], p < 0.01), and an increase in total plasma bilirubin (8.19% [0.79, 15.59], p < 0.01), comparing with placebo or other oral antidiabetic drugs. SGLT2 inhibitors treatment was associated with a decrease in liver steatosis (-3.39% [-6.01, -0.77], p < 0.0.1). CONCLUSIONS Treatment with SGLT2 inhibitors improves liver structure and function in patients with T2D. This meta-analysis suggests that SGLT2 inhibitors are a promising pharmacological approach for treatment of NAFLD.
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Affiliation(s)
- Francisca Dos Santos Coelho
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Marta Borges-Canha
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Madalena von Hafe
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - João Sérgio Neves
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Catarina Vale
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Ana Rita Leite
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Davide Carvalho
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3s), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Adelino Leite-Moreira
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Cirurgia Cardiotorácica, Centro Hospitalar Universitário de São João, Porto, Portugal
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Jaikumkao K, Promsan S, Thongnak L, Swe MT, Tapanya M, Htun KT, Kothan S, Intachai N, Lungkaphin A. Dapagliflozin ameliorates pancreatic injury and activates kidney autophagy by modulating the AMPK/mTOR signaling pathway in obese rats. J Cell Physiol 2021; 236:6424-6440. [PMID: 33559163 DOI: 10.1002/jcp.30316] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/30/2020] [Accepted: 01/27/2021] [Indexed: 02/05/2023]
Abstract
Chronic consumption of a high-fat diet induces obesity and impairs the ultra-structure of organs and tissues. We examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor-dapagliflozin on renal and pancreatic injuries in obese condition. Rats were fed a high-fat diet for 16 weeks to induce obesity. After that, dapagliflozin or vildagliptin, 1.0 or 3.0 mg/kg/day, respectively, was administered by oral gavage for 4 weeks. The effects of dapagliflozin on insulin resistance, kidney autophagy, pancreatic oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis in high-fat diet-induced obese rats were elucidated. High-fat-diet fed rats demonstrated metabolic abnormalities including increased body weight, visceral fat weight, plasma insulin, plasma cholesterol, homeostasis model assessment (HOMA) index, and TAUCg, indicating the obese-insulin resistant and glucose intolerance conditions. Also, high-fat-diet fed rats exhibited significant pancreatic injury accompanied by decreased kidney autophagy. Dapagliflozin or vildagliptin treatment for 4 weeks ameliorated pancreatic oxidative stress, ER stress, inflammation, and apoptosis and restored kidney autophagy in obese rats. Moreover, the morphology changes of the pancreas and kidney were improved in the treated groups. Interestingly, dapagliflozin showed higher efficacy than vildagliptin in improving body weight, visceral fat weight, plasma cholesterol level, and pancreatic oxidative stress in our model. Taken together, the present study demonstrated that the therapeutic effects of dapagliflozin attenuated pancreatic injury, pancreatic oxidative stress, ER stress, inflammation, apoptosis, and exerted renoprotective effects by restoring autophagic signaling in obese rats.
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Affiliation(s)
- Krit Jaikumkao
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Center of Radiation Research and Medical Imaging, Chiang Mai University, Chiang Mai, Thailand
| | - Sasivimon Promsan
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Laongdao Thongnak
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Myat T Swe
- Department of Physiology, University of Medicine 2, Yangon, Yangon, Myanmar
| | - Monruedee Tapanya
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Khin T Htun
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Suchart Kothan
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Center of Radiation Research and Medical Imaging, Chiang Mai University, Chiang Mai, Thailand
| | - Nuttawadee Intachai
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Das C, Tripathy D, Swain S, Sudhakaran N, Uthansingh K, Mallick P, Pati GK. Effect of Dapagliflozin on Type 2 Diabetes Mellitus With Nonalcoholic Fatty Liver Disease: A Single-Center Survey. Cureus 2021; 13:e14974. [PMID: 34123670 PMCID: PMC8192310 DOI: 10.7759/cureus.14974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 20%-40%. Approximately 40%-60% of patients with type 2 diabetes mellitus (DM2) experience NAFLD; out of which 20%-40% cases may have higher severity. Due to the scarcity of available reports from the eastern part of India, we aimed to evaluate the effects of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor used in these types of cases. Material and methods The study included consecutive patients with DM2 and NAFLD, treated with dapagliflozin at 10 mg daily for six months. All patients underwent detailed anthropometric, biochemical, abdominal ultrasonography, and transient elastography studies at baseline and after therapy as well as a comparative analysis. Results In the 100 patients included in our study, the male patients outnumbered the female patients (male-to-female ratio, 4.27:-1) and the mean age at presentation was 44.11 ± 8.24 years. The mean body mass index significantly decreased over the course of the therapy, from 27.31± 1.87 kg/m2 at baseline to 26.21 ± 1.51 kg/m2 after the therapy. The patients’ transaminitis, dyslipidemia, and glycemic status significantly improved over the course of the therapy. We also observed significant (p < 0.05) improvement in hepatic steatosis by the end of the treatment. Although transient elastography by FibroScan-measured hepatic fibrosis score (Echosens, Paris, France) significantly decreased from 6.95 ± 1.42 to 6 ± 1.44 kPa, hepatic fibrosis did not improve significantly (p ≥ 0.05) following therapy. Conclusion Although dapagliflozin improved body mass index, transaminitis, dyslipidemia, glycemic status, and hepatic steatosis, it had a minimal effect on hepatic fibrosis.
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Affiliation(s)
- Chandan Das
- Department of Medicine, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, IND
| | - Debasmita Tripathy
- Department of Medicine, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, IND
| | - Surendranath Swain
- Department of Medicine, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, IND
| | - Navin Sudhakaran
- Department of Medicine, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, IND
| | - Kanishka Uthansingh
- Department of Gastroenterology and Hepatobiliary Sciences, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, IND
| | - Pradeep Mallick
- Department of Gastroenterology and Hepatobiliary Sciences, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar, IND
| | - Girish K Pati
- Department of Gastroenterology and Hepatobiliary Sciences, Institute of Medical Sciences and SUM Hospital, Bhubaneshwar, IND
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Kralova E, Marusakova M, Hadova K, Krenek P, Klimas J. Dapagliflozin elevates plasma high-density lipoprotein levels and influences visceral fat gene expression in streptozotocin-induced diabetes mellitus. J Pharm Pharmacol 2021; 73:778-784. [PMID: 33749792 DOI: 10.1093/jpp/rgab005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/13/2021] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Dapagliflozin (Dapa) could potentially be used to treat type 1 diabetes mellitus. We tested the hypothesis that it would influence blood lipid levels and visceral fat accumulation in a rodent diabetic model. METHODS We used three groups of male Wistar rats: Controls, streptozotocin (STZ)-treated rats and STZ-treated orally with Dapa (STZ+Dapa), 10 mg/kg/day for six weeks. Blood glucose and serum lipids levels were determined. Plasma levels of lipases (hormone-sensitive lipase, HSL and lipoprotein lipase, LPL), adipokines (leptin and adiponectin) and proinflammatory cytokines [tumour necrosis factor-alpha (TNFα) and interleukin-6 (IL-6)] were determined by ELISA assays. mRNA levels in the perirenal fat were determined by real-time PCR. KEY FINDINGS Dapa suppressed STZ-related hyperglycemia by 20% (P < 0.05) and increased serum HDL when compared to the controls and the STZ-only treated rats (both P < 0.05). STZ treatment caused elevations of other serum lipids that were resistant to Dapa treatment. Dapa treatment also increased both plasma and visceral fat mRNA levels of leptin, LPL and IL-6, while decreasing plasma and fat expressions of HSL and TNFα compared to the STZ-only treated rats (all P < 0.05). CONCLUSIONS Our results suggest that Dapa, in addition to its antidiabetic effect, also influences the function of adipose tissue which could be beneficial in the treatment of diabetes.
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Affiliation(s)
- Eva Kralova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Margareta Marusakova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Katarina Hadova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Peter Krenek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
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SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits. Int J Mol Sci 2021; 22:ijms22094441. [PMID: 33922865 PMCID: PMC8122991 DOI: 10.3390/ijms22094441] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022] Open
Abstract
In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs.
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Takata T, Isomoto H. Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control. Int J Mol Sci 2021; 22:ijms22094374. [PMID: 33922132 PMCID: PMC8122753 DOI: 10.3390/ijms22094374] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 04/14/2021] [Accepted: 04/20/2021] [Indexed: 12/30/2022] Open
Abstract
Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.
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Cohen A, Ioannidis K, Ehrlich A, Regenbaum S, Cohen M, Ayyash M, Tikva SS, Nahmias Y. Mechanism and reversal of drug-induced nephrotoxicity on a chip. Sci Transl Med 2021; 13:eabd6299. [PMID: 33627489 PMCID: PMC8897043 DOI: 10.1126/scitranslmed.abd6299] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/30/2020] [Accepted: 01/13/2021] [Indexed: 12/12/2022]
Abstract
The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures.
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Affiliation(s)
- Aaron Cohen
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
- Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Konstantinos Ioannidis
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Avner Ehrlich
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
- Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Shaun Regenbaum
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
- Tissue Dynamics, Jerusalem 91904, Israel
| | - Merav Cohen
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
- Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
| | - Muneef Ayyash
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
- Tissue Dynamics, Jerusalem 91904, Israel
| | | | - Yaakov Nahmias
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
- Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
- Tissue Dynamics, Jerusalem 91904, Israel
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Impact of an SGLT2-loss of function mutation on renal architecture, histology, and glucose homeostasis. Cell Tissue Res 2021; 384:527-543. [PMID: 33409652 DOI: 10.1007/s00441-020-03358-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 11/18/2020] [Indexed: 01/14/2023]
Abstract
Inhibitors of sodium/glucose co-transporter 2 (SGLT2) are currently in clinical use for type 2 diabetes (T2D) treatment due to their anti-hyperglycemic effect exerted by the inhibition of glucose reabsorption in the kidney. Inhibition of SGLT2 is associated with improvement of renal outcomes in chronic kidney disease associated with T2D. Our study aimed to describe the renal-specific phenotypic consequences of the SGLT2-loss of function "Jimbee" mutation within the Slc5a2 mouse gene in a non-diabetic/non-obese background. The Jimbee mice displayed reduced body weight, glucosuria, polyuria, polydipsia, and hyperphagia but were normoglycemic, with no signs of baseline insulin resistance or renal dysfunction. Histomorphological analysis of the kidneys revealed a normal architecture and morphology of the renal cortex, but shrinkage of the glomerular and tubular apparatus, including Bowman's space, glomerular tuft, mesangial matrix fraction, and proximal convoluted tubule (PCT). Immunofluorescent analysis of renal sections showed that SGLT2 was absent from the apical membrane of PCT of the Jimbee mice but remnant positive vesicles were detected within the cytosol or at the perinuclear interface. Renal localization and abundance of GLUT1, GLUT2, and SGLT1 were unchanged in the Jimbee genotype. Intriguingly, the mutation did not induce hepatic gluconeogenic gene expression in overnight fasted mice despite a high glucose excretion rate. The Jimbee phenotype is remarkably similar to humans with SLC5A2 mutations and provides a useful model for the study of SGLT2-loss of function effects on renal architecture and physiology, as well as for identifying possible novel roles for the kidneys in glucose homeostasis and metabolic reprogramming.
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Cansby E, Caputo M, Gao L, Kulkarni NM, Nerstedt A, Ståhlman M, Borén J, Porosk R, Soomets U, Pedrelli M, Parini P, Marschall HU, Nyström J, Howell BW, Mahlapuu M. Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease. JCI Insight 2020; 5:140483. [PMID: 33170807 PMCID: PMC7819747 DOI: 10.1172/jci.insight.140483] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 11/04/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.
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Affiliation(s)
| | - Mara Caputo
- Department of Chemistry and Molecular Biology and
| | - Lei Gao
- Department of Chemistry and Molecular Biology and
| | | | | | - Marcus Ståhlman
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jan Borén
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Rando Porosk
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia
| | - Ursel Soomets
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia
| | | | - Paolo Parini
- Department of Laboratory Medicine and.,Metabolism Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Theme Inflammation and Infection, Karolinska University Hospital, Stockholm, Sweden
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jenny Nyström
- Department of Physiology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Brian W Howell
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, USA
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Effects of antidiabetic drugs that cause glucose excretion directly from the body on mortality. MEDICINE IN DRUG DISCOVERY 2020. [DOI: 10.1016/j.medidd.2020.100062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Gameil MA, Abdelgawad MS, Bahgat MH, Elsebaie AH, Marzouk RE. Influence of sodium glucose co-transporter 2 inhibitors on fatty liver index parameters in type 2 diabetes mellitus. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2020. [DOI: 10.1186/s43162-020-00013-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) represents a major public health challenge worldwide. It affects more than half of the patients with type 2 diabetes mellitus (T2D). It may progress to non-alcoholic steatohepatitis, cirrhosis, and carcinoma. The sodium glucose co-transporter 2 inhibitors (SGLT2 inhibitors) may improve hepatic steatosis. We aimed to estimate the effect of empagliflozin or dapagliflozin versus conventional treatment on fatty liver status in patients with concomitant T2D and NAFLD over 24 weeks.
Results
We found a significant improvement of the fatty liver index (FLI) with a significant reduction of the bodyweight, body mass index, waist circumference, ALT, AST, GGT, AST to ALT ratio, lipid profile, and lipid profile ratios in both SGLT2 inhibitors groups versus the conventional treatment group. Post hoc analysis revealed no statistically significant difference between the SGLT2 inhibitors groups (dapagliflozin versus empagliflozin).
Conclusion
SGLT2 inhibitors, empagliflozin and dapagliflozin, exert a beneficial effect on the fatty liver index of diabetic patients with NAFLD.
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Factors Associated with the Remission of Type 1 Diastolic Dysfunction after Dapagliflozin Treatment in Patients with Type 2 Diabetes. J Clin Med 2020; 9:jcm9113779. [PMID: 33238573 PMCID: PMC7700333 DOI: 10.3390/jcm9113779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/17/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
Patients with type 2 diabetes (T2DM) are at high risk of developing cardiovascular disease and heart failure (HF), both with preserved and reduced ejection fraction of the left ventricle. Previous research demonstrated that dapagliflozin treatment is associated with the remission of type 1 diastolic dysfunction (DD1) in patients with T2DM. The main aim of this study was to evaluate the possible baseline predictors associated with the remission of DD1 in patients with T2D after one year of dapagliflozin treatment. In this prospective and observational study, 45 patients with T2DM were evaluated before and after one year of treatment with 10 mg dapagliflozin daily added to their background therapy. In the studied group, 73.3% (33/45) of the patients had DD1 at baseline. The primary outcome of this research was DD1 remission. DD1 remission was associated with improvement of liver stiffness, an increase in estimated glomerular filtration rate (eGFR), and a decrease in hemoglobin A1c (HbA1c). Independent predictors for the remission of DD1 were a more than 0.4 kPa difference in the initial stiffness score and the 1-year assessment fibrosis score and a duration of diabetes ≤8 years. Age, body mass index (BMI), or patient weight after one year did not influence the DD1 outcome. Patients with a T2DM duration of less than eight years have the additional benefit of DD1 remission associated with dapagliflozin treatment beyond the conventional benefits such as improvements in glycemic control, cardiovascular, renal, and hepatic risk reductions. In patients with T2DM, the remission of DD1 was associated with decrease of liver stiffness.
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Potential anti-inflammatory effect of dapagliflozin in HCHF diet- induced fatty liver degeneration through inhibition of TNF-α, IL-1β, and IL-18 in rat liver. Int Immunopharmacol 2020; 86:106730. [DOI: 10.1016/j.intimp.2020.106730] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/01/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
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50
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Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice. Int J Mol Sci 2020; 21:ijms21114054. [PMID: 32517059 PMCID: PMC7312919 DOI: 10.3390/ijms21114054] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022] Open
Abstract
Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i–HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.
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