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Liu N, Yan WT, Xiong K. Exploring a novel mechanism for targeting β-arrestin-2 in the management of diabetic nephropathy. World J Diabetes 2025; 16:101994. [DOI: 10.4239/wjd.v16.i4.101994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/04/2025] [Accepted: 02/10/2025] [Indexed: 02/28/2025] Open
Abstract
Diabetic nephropathy (DN) is a well-known microvascular complication in patients with diabetes mellitus, which is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments, along with the hyalinization of intrarenal vasculature. DN has recently emerged as a leading cause of chronic and end-stage renal disease. While the pathobiology of other diabetic microvascular complications, such as retinopathy, is largely understood and has reasonable therapeutic options, the mechanisms and management strategies for DN remain incompletely elucidated. In this editorial, we comment on the article by Liu et al, focusing on the mechanisms underlying the detrimental impact of β-arrestin-2 on the kidneys in the context of DN. The authors suggest that inhibiting β-arrestin-2 could alleviate renal damage through suppressing apoptosis of glomerular endothelial cells (GENCs), highlighting β-arrestin-2 as a promising therapeutic target for DN. The study proposed that β-arrestin-2 triggers endoplasmic reticulum (ER) stress via the ATF6 signaling pathway, thereby promoting GENC apoptosis and exacerbating DN progression. Given the novel and crucial role of β-arrestin-2 in ER stress-related DN, it is imperative to further explore β-arrestin-2, its roles in ER stress and the potential therapeutic implications in DN.
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Affiliation(s)
- Na Liu
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Wei-Tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
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Lv J, Yu H, Du S, Xu P, Zhao Y, Qi W, Wang X. Targeting endoplasmic reticulum stress: an innovative therapeutic strategy for podocyte-related kidney diseases. J Transl Med 2025; 23:95. [PMID: 39838496 PMCID: PMC11752968 DOI: 10.1186/s12967-025-06076-3] [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: 09/29/2024] [Accepted: 01/03/2025] [Indexed: 01/23/2025] Open
Abstract
The endoplasmic reticulum (ER) is a vital organelle responsible for protein quality control, including the folding, modification, and transport of proteins. When misfolded or unfolded proteins accumulate in the ER, it triggers endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) to restore ER homeostasis. However, prolonged or excessive ERS can lead to apoptosis. The kidneys play a crucial role in maintaining physiological functions by excreting metabolic waste, regulating blood volume, balancing electrolytes and acid-base levels, and secreting various bioactive substances. Podocytes, epithelial cells situated outside the glomerular basement membrane, are essential for maintaining the structural integrity and permeability of the glomerular filtration barrier. Previous studies have shown that ERS in podocytes can contribute to the development of diseases such as glomerulonephritis, hereditary nephropathy, and diabetic kidney disease, potentially progressing to end-stage renal disease and causing patient mortality. As such, investigating ERS in podocytes has become a key area of focus in kidney disease research. This study examines recent advancements in understanding the effects of excessive ERS on podocytes across various kidney diseases, highlights the role of podocyte ERS in disease progression, and explores the potential therapeutic benefits of targeting the UPR to manage ERS in kidney diseases, thereby providing a scientific basis for clinical interventions.
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Affiliation(s)
- Jiao Lv
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Honghai Yu
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Sasa Du
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Pengyu Xu
- College of Acupuncture and Moxibustion, Changchun University of Traditional Chinese Medicine, Changchun, 130117, China
| | - Yunyun Zhao
- Endocrinology Department, First Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Wenxiu Qi
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Ministry of Education, Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Xiuge Wang
- Endocrinology Department, First Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130021, China.
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Liu F, Yang Z, Li J, Wu T, Li X, Zhao L, Wang W, Yu W, Zhang G, Xu Y. Targeting programmed cell death in diabetic kidney disease: from molecular mechanisms to pharmacotherapy. Mol Med 2024; 30:265. [PMID: 39707216 DOI: 10.1186/s10020-024-01020-5] [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: 09/23/2024] [Accepted: 11/29/2024] [Indexed: 12/23/2024] Open
Abstract
Diabetic kidney disease (DKD), one of the most prevalent microvascular complications of diabetes, arises from dysregulated glucose and lipid metabolism induced by hyperglycemia, resulting in the deterioration of renal cells such as podocytes and tubular epithelial cells. Programmed cell death (PCD), comprising apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis, represents a spectrum of cell demise processes intricately governed by genetic mechanisms in vivo. Under physiological conditions, PCD facilitates the turnover of cellular populations and serves as a protective mechanism to eliminate impaired podocytes or tubular epithelial cells, thereby preserving renal tissue homeostasis amidst hyperglycemic stress. However, existing research predominantly elucidates individual modes of cell death, neglecting the intricate interplay and mutual modulation observed among various forms of PCD. In this comprehensive review, we delineate the diverse regulatory mechanisms governing PCD and elucidate the intricate crosstalk dynamics among distinct PCD pathways. Furthermore, we review recent advancements in understanding the pathogenesis of PCD and explore their implications in DKD. Additionally, we explore the potential of natural products derived primarily from botanical sources as therapeutic agents, highlighting their multifaceted effects on modulating PCD crosstalk, thereby proposing novel strategies for DKD treatment.
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Affiliation(s)
- Fengzhao Liu
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Zhenyu Yang
- Graduate School of Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Jixin Li
- Xi Yuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Tao Wu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiangyu Li
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Lijuan Zhao
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Wenru Wang
- Xi Yuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wenfei Yu
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Guangheng Zhang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Yunsheng Xu
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, China.
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Min L, Chen Y, Chen Y, Zhong F, Ni Z, Gu L, Lee K, He JC. RTN1A mediates diabetes-induced AKI-to-CKD transition. JCI Insight 2024; 9:e185826. [PMID: 39704174 DOI: 10.1172/jci.insight.185826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/05/2024] [Indexed: 12/21/2024] Open
Abstract
Diabetic patients have increased susceptibility to acute kidney injury (AKI), and AKI could progress to chronic tubulointerstitial injury and fibrosis, referred to as AKI-to-chronic kidney disease (AKI-to-CKD) transition. However, whether diabetes directly promotes AKI-to-CKD transition is not known. We previously showed that reticulon-1A (RTN1A), a gene highly upregulated in injured renal tubular epithelial cells (RTECs), promotes AKI-to-CKD transition in nondiabetic settings. Therefore, we also examined whether reducing RTN1A expression could attenuate diabetes-induced AKI-to-CKD transition. Diabetes was induced by a high-fat diet and streptozotocin injections, and unilateral ischemic reperfusion injury was created as an AKI model in control, diabetic, and RTEC-specific Rtn1a-knockdown diabetic mice. AKI induced greater renal function decline, tubulointerstitial injury, and fibrosis in diabetic mice than in nondiabetic mice. Reduction of RTN1A markedly reduced the CKD development following AKI in diabetic mice, which was associated with reduced ER stress and mitochondrial dysfunction in RTECs. These findings indicate that diabetes markedly accelerates AKI-to-CKD transition and that RTN1A is a crucial mediator of diabetes-induced AKI-to-CKD transition. The development of RTN1A inhibitors could potentially attenuate AKI-to-CKD transition in diabetic patients.
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Affiliation(s)
- Lulin Min
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ya Chen
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yixin Chen
- Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Fang Zhong
- Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Leyi Gu
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kyung Lee
- Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - John Cijiang He
- Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Renal Section, James J. Peters Veterans Affair Medical Center, Bronx, New York, USA
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Duara J, Torres M, Gurumani M, Molina David J, Njeim R, Kim JJ, Mitrofanova A, Ge M, Sloan A, Müller-Deile J, Schiffer M, Merscher S, Fornoni A. Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria. Am J Physiol Renal Physiol 2024; 327:F340-F350. [PMID: 38961844 PMCID: PMC11460532 DOI: 10.1152/ajprenal.00319.2023] [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: 10/09/2023] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 07/05/2024] Open
Abstract
Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein-like 7 (OSBPL7) modulates the expression and function of ATP-binding cassette subfamily A member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Using mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. Although as expected, the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7 deficiency-related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7 deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target.NEW & NOTEWORTHY OSBPL7 and ER stress comprise a central mechanism in glomerular injury. This study highlights a crucial link between OSBPL7 deficiency and ER stress in CKD. OSBPL7 deficiency causes ER stress, leading to podocyte apoptosis. There is a selective effect on lipid homeostasis in that OSBPL7 deficiency affects lipid homeostasis, altering cellular triglyceride but not cholesterol content. The interaction of ER stress and apoptosis supports that ER stress, not reduced autophagy, is the main driver of apoptosis in OSBPL7-deficient podocytes.
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Affiliation(s)
- Joanne Duara
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Department of Pediatrics/Division of Neonatology, Batchelor Children's Research Institute, Holtz Children's Hospital, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Maria Torres
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Boston University, Boston, Massachusetts, United States
| | - Margaret Gurumani
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Boston University, Boston, Massachusetts, United States
| | - Judith Molina David
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Rachel Njeim
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Jin-Ju Kim
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Alla Mitrofanova
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Mengyuan Ge
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Alexis Sloan
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Janina Müller-Deile
- Department of Nephrology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Mount Desert Island Biological Laboratories, Salisbury Cove, Maine, United States
| | - Sandra Merscher
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, United States
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
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von Rauchhaupt E, Klaus M, Ribeiro A, Honarpisheh M, Li C, Liu M, Köhler P, Adamowicz K, Schmaderer C, Lindenmeyer M, Steiger S, Anders HJ, Lech M. GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation. Cells 2024; 13:637. [PMID: 38607075 PMCID: PMC11011265 DOI: 10.3390/cells13070637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/22/2024] [Accepted: 03/30/2024] [Indexed: 04/13/2024] Open
Abstract
GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.
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Affiliation(s)
- Ekaterina von Rauchhaupt
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Martin Klaus
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Andrea Ribeiro
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
- Klinikum Rechts der Isar, Department of Nephrology, Technical University Munich, 81675 Munich, Germany;
| | - Mohsen Honarpisheh
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Chenyu Li
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Min Liu
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Paulina Köhler
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Karina Adamowicz
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, 30-387 Krakow, Poland;
| | - Christoph Schmaderer
- Klinikum Rechts der Isar, Department of Nephrology, Technical University Munich, 81675 Munich, Germany;
| | - Maja Lindenmeyer
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
| | - Stefanie Steiger
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Hans-Joachim Anders
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
| | - Maciej Lech
- Department of Medicine IV, Renal Division, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany; (E.v.R.); (M.K.); (A.R.); (M.H.); (C.L.); (M.L.); (P.K.); (S.S.); (H.-J.A.)
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He YX, Wang T, Li WX, Chen YX. Long noncoding RNA protein-disulfide isomerase-associated 3 regulated high glucose-induced podocyte apoptosis in diabetic nephropathy through targeting miR-139-3p. World J Diabetes 2024; 15:260-274. [PMID: 38464366 PMCID: PMC10921158 DOI: 10.4239/wjd.v15.i2.260] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/13/2023] [Accepted: 01/15/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Podocyte apoptosis plays a vital role in proteinuria pathogenesis in diabetic nephropathy (DN). The regulatory relationship between long noncoding RNAs (lncRNAs) and podocyte apoptosis has recently become another research hot spot in the DN field. AIM To investigate whether lncRNA protein-disulfide isomerase-associated 3 (Pdia3) could regulate podocyte apoptosis through miR-139-3p and revealed the underlying mechanism. METHODS Using normal glucose or high glucose (HG)-cultured podocytes, the cellular functions and exact mechanisms underlying the regulatory effects of lncRNA Pdia3 on podocyte apoptosis and endoplasmic reticulum stress (ERS) were explored. LncRNA Pdia3 and miR-139-3p expression were measured through quantitative real-time polymerase chain reaction. Relative cell viability was detected through the cell counting kit-8 colorimetric assay. The podocyte apoptosis rate in each group was measured through flow cytometry. The interaction between lncRNA Pdia3 and miR-139-3p was examined through the dual luciferase reporter assay. Finally, western blotting was performed to detect the effect of lncRNA Pdia3 on podocyte apoptosis and ERS via miR-139-3p. RESULTS The expression of lncRNA Pdia3 was significantly downregulated in HG-cultured podocytes. Next, lncRNA Pdia3 was involved in HG-induced podocyte apoptosis. Furthermore, the dual luciferase reporter assay confirmed the direct interaction between lncRNA Pdia3 and miR-139-3p. LncRNA Pdia3 overexpression attenuated podocyte apoptosis and ERS through miR-139-3p in HG-cultured podocytes. CONCLUSION Taken together, this study demonstrated that lncRNA Pdia3 overexpression could attenuate HG-induced podocyte apoptosis and ERS by acting as a competing endogenous RNA of miR-139-3p, which might provide a potential therapeutic target for DN.
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Affiliation(s)
- Yin-Xi He
- Department of Orthopaedic Trauma, The Third Hospital of Shijiazhuang, Shijiazhuang 050000, Hebei Province, China
| | - Ting Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Wen-Xian Li
- Department of Endocrinology, The First Hospital of Zhangjiakou, Zhangjiakou 075000, Hebei Province, China
| | - Yan-Xia Chen
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Wang G, Deng J, Hua Z. Crocin protects against endoplasmic reticulum stress-related tubular injury in diabetic nephropathy via the activation of the PI3K/AKT/Nrf2 pathway. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:439-446. [PMID: 38419890 PMCID: PMC10897564 DOI: 10.22038/ijbms.2023.73385.15942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/26/2023] [Indexed: 03/02/2024]
Abstract
Objectives Diabetic nephropathy (DN) is the main cause of end-stage renal disease, but the current treatment is not satisfactory. Crocin is a major bioactive compound of saffron with antioxidant and anti-endoplasmic reticulum stress (ERS) abilities used to treat diabetes. This study specifically investigated whether crocin has a regulatory role in renal injury in DN. Materials and Methods The experiment was divided into control, (db/m mice), model (db/db mice), and experimental groups (db/db mice were intraperitoneally injected with 40 mg/kg crocin). Renal function-related indicators (Scr, BUN, FBG, UP, TG, TC, ALT, and AST) and oxidative stress-related indicators (ROS, MDA, GSH, SOD, and CAT) were assessed. The pathological changes of renal tissues were confirmed by HE, Masson, PAS, and TUNEL staining. The levels of ERS-related proteins (GRP78 and CHOP), apoptosis-related proteins, and PI3K/AKT and Nrf2 pathways-related proteins in renal tissue were detected. Results In db/db mice, renal function-related indicators, apoptotic cells of renal tissues, the contents of ROS and MDA as well as the expressions of CHOP, GRP78, and Bax were increased, the degree of renal tissue damage was aggravated, while the contents of GSH, SOD, and CAT, as well as the protein levels of Nrf2, PARP, anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-xl) were decreased compared to the db/m mice. However, crocin treatment reversed the above-mentioned situation. The expressions of the PI3K/AKT and Nrf2 pathways-related proteins were also activated by crocin. Conclusion Crocin inhibited oxidative stress and ERS-induced kidney injury in db/db mice by activating the PI3K/AKT and Nrf2 pathways.
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Affiliation(s)
- Guiying Wang
- Department of Nephrology, Shangyu People's Hospital of Shaoxing, Shaoxing, China
| | - Jiuhon Deng
- Department of Endocrinology, Second People's Hospital of Pingyang County, Wenzhou, China
| | - Zhou Hua
- Department of Nephrology, The People's Hospital of Suichang County, Lishui, China
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Li J, Huang Z, Jin Y, Liang L, Li Y, Xu K, Zhou W, Li X. Neuroprotective Effect of Tauroursodeoxycholic Acid (TUDCA) on In Vitro and In Vivo Models of Retinal Disorders: A Systematic Review. Curr Neuropharmacol 2024; 22:1374-1390. [PMID: 37691227 PMCID: PMC11092919 DOI: 10.2174/1570159x21666230907152207] [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: 10/23/2022] [Revised: 02/15/2023] [Accepted: 03/07/2023] [Indexed: 09/12/2023] Open
Abstract
BACKGROUND Tauroursodeoxycholic acid (TUDCA) is a naturally produced hydrophilic bile acid that has been used for centuries in Chinese medicine. Numerous recent in vitro and in vivo studies have shown that TUDCA has neuroprotective action in various models of retinal disorders. OBJECTIVE To systematically review the scientific literature and provide a comprehensive summary on the neuroprotective action and the mechanisms involved in the cytoprotective effects of TUDCA. METHODS A systematic review was conducted in accordance with the PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Systematic literature search of United States National Library of Medicine (PubMed), Web of Science, Embase, Scopus and Cochrane Library was performed, which covered all original articles published up to July 2022. The terms, "TUDCA" in combination with "retina", "retinal protection", "neuroprotection" were searched. Possible biases were identified with the adopted SYRCLE's tool. RESULTS Of the 423 initially gathered studies, 24 articles met inclusion/exclusion criteria for full-text review. Six of them were in vitro experiments, 17 studies reported in vivo data and one study described both in vitro and in vivo data. The results revealed the effect of TUDCA on different retinal diseases, such as retinitis pigmentosa (RP), diabetic retinopathy (DR), retinal degeneration (RD), retinal ganglion cell (RGC) injury, Leber's hereditary optic neuropathy (LHON), choroidal neovascularization (CNV), and retinal detachment (RDT). The quality scores of the in vivo studies were ranged from 5 to 7 points (total 10 points), according to SYRCLE's risk of bias tool. Both in vitro and in vivo data suggested that TUDCA could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and function, and its mechanism of actions might be related with inhibiting apoptosis, decreasing inflammation, attenuating oxidative stress, suppressing endoplasmic reticulum (ER) stress, and reducing angiogenesis. CONCLUSION This systematic review demonstrated that TUDCA has neuroprotective effect on in vivo and in vitro models of retinal disorders, reinforcing the currently available evidence that TUDCA could be a promising therapeutic agent in retinal diseases treatment. However, well designed clinical trials are necessary to appraise the efficacy of TUDCA in clinical setting.
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Affiliation(s)
- Jiaxian Li
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Ziyang Huang
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Yu Jin
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Lina Liang
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Yamin Li
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Kai Xu
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Wei Zhou
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
| | - Xiaoyu Li
- Department of Eye Function Laboratory, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing 100040, China
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Yang C, Zhang Z, Liu J, Chen P, Li J, Shu H, Chu Y, Li L. Research progress on multiple cell death pathways of podocytes in diabetic kidney disease. Mol Med 2023; 29:135. [PMID: 37828444 PMCID: PMC10571269 DOI: 10.1186/s10020-023-00732-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 09/18/2023] [Indexed: 10/14/2023] Open
Abstract
Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, and renal failure. The injury and death of glomerular podocytes are the keys to DKD. Currently, a variety of cell death modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. The signaling pathways leading to these cell death processes are interconnected and can be activated simultaneously or in parallel. They are essential for cell survival and death that determine the fate of cells. With the deepening of the research on the mechanism of cell death, more and more researchers have devoted their attention to the underlying pathologic research and the drug therapy research of DKD. In this paper, we discussed the podocyte physiologic role and DKD processes. We also provide an overview of the types and specific mechanisms involved in each type of cell death in DKD, as well as related targeted therapy methods and drugs are reviewed. In the last part we discuss the complexity and potential crosstalk between various modes of cell death, which will help improve the understanding of podocyte death and lay a foundation for new and ideal targeted therapy strategies for DKD treatment in the future.
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Affiliation(s)
- Can Yang
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Zhen Zhang
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China
- School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Jieting Liu
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Peijian Chen
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Jialing Li
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Haiying Shu
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China
| | - Yanhui Chu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China.
| | - Luxin Li
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, 157000, China.
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China.
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Yu Q, Chen Y, Zhao Y, Huang S, Xin X, Jiang L, Wang H, Wu W, Qu L, Xiang C, Wang S, Liu G, Yang L. Nephropathy Is Aggravated by Fatty Acids in Diabetic Kidney Disease through Tubular Epithelial Cell Necroptosis and Is Alleviated by an RIPK-1 Inhibitor. KIDNEY DISEASES (BASEL, SWITZERLAND) 2023; 9:408-423. [PMID: 37927402 PMCID: PMC10624943 DOI: 10.1159/000529995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/16/2023] [Indexed: 11/07/2023]
Abstract
Introduction Diabetic kidney disease (DKD), one of the leading causes of end-stage renal disease, has complex pathogenic mechanisms and few effective clinical therapies. DKD progression is accompanied by the loss of renal resident cells, followed by chronic inflammation and extracellular matrix deposition. Necroptosis is a newly discovered form of regulated cell death and is a major form of intrinsic cell loss in certain diabetic complications such as cardiomyopathy, intestinal disease, and retinal neuropathy; however, its significance in DKD is largely unknown. Methods In this study, the expression of necroptosis marker phosphorylated MLKL (p-MLKL) in renal biopsy tissues of patients with DKD was detected using immunofluorescence and semiquantified using immunohistochemistry. The effects of different disease-causing factors on necroptosis activation in human HK-2 cells were evaluated using immunofluorescence and Western blotting. db/db diabetic mice were fed a high-fat diet to establish an animal model of DKD with significant renal tubule damage. Mice were treated with the RIPK1 inhibitor RIPA-56 to evaluate its renal protective effects. mRNA transcriptome sequencing was used to explore the changes in signaling pathways after RIPA-56 treatment. Oil red O staining and electron macroscopy were used to observe lipid droplet accumulation in renal biopsy tissues and mouse kidney tissues. Results Immunostaining of phosphorylated RIPK1/RIPK3/MLKL verified the occurrence of necroptosis in renal tubular epithelial cells of patients with DKD. The level of the necroptosis marker p-MLKL correlated positively with the severity of renal functional, pathological damages, and lipid droplet accumulation in patients with DKD. High glucose and fatty acids were the main factors causing necroptosis in human renal tubular HK-2 cells. Renal function deterioration and renal pathological injury were accelerated, and the necroptosis pathway was activated in db/db mice fed a high-fat diet. Application of RIPA-56 effectively reduced the degree of renal injury, inhibited the necroptosis pathway activation, and reduced necroinflammation and lipid droplet accumulation in the renal tissues of db/db mice fed a high-fat diet. Conclusion The present study revealed the role of necroptosis in the progression of DKD and might provide a new therapeutic target for the treatment of DKD.
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Affiliation(s)
- Qi Yu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Ying Chen
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Youlu Zhao
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuo Huang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Xiaohong Xin
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Lei Jiang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Wenyan Wu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Lei Qu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Chengang Xiang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Suxia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Gang Liu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li Yang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Liu Y, Qiao Y, Pan S, Chen J, Mao Z, Ren K, Yang Y, Feng Q, Liu D, Liu Z. Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease. Int J Biol Sci 2023; 19:4427-4441. [PMID: 37781026 PMCID: PMC10535705 DOI: 10.7150/ijbs.86608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 08/15/2023] [Indexed: 10/03/2023] Open
Abstract
Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.
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Affiliation(s)
- Yong Liu
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
| | - Yingjin Qiao
- Blood Purification Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Shaokang Pan
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
| | - Jingfang Chen
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
| | - Zihui Mao
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
| | - Kaidi Ren
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Yang Yang
- Clinical Systems Biology Laboratories, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
| | - Qi Feng
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
| | - Dongwei Liu
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
| | - Zhangsuo Liu
- Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, P. R. China
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Wei M, Liu X, Li M, Tian X, Feng M, Pang B, Fang Z, Wei J. The role of Chinese herbal medicine in the treatment of diabetic nephropathy by regulating endoplasmic reticulum stress. Front Pharmacol 2023; 14:1174415. [PMID: 37435493 PMCID: PMC10331427 DOI: 10.3389/fphar.2023.1174415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 06/15/2023] [Indexed: 07/13/2023] Open
Abstract
Diabetic nephropathy (DN), a prevalent microvascular complication of diabetes mellitus, is the primary contributor to end-stage renal disease in developed countries. Existing clinical interventions for DN encompass lifestyle modifications, blood glucose regulation, blood pressure reduction, lipid management, and avoidance of nephrotoxic medications. Despite these measures, a significant number of patients progress to end-stage renal disease, underscoring the need for additional therapeutic strategies. The endoplasmic reticulum (ER) stress response, a cellular defense mechanism in eukaryotic cells, has been implicated in DN pathogenesis. Moderate ER stress can enhance cell survival, whereas severe or prolonged ER stress may trigger apoptosis. As such, the role of ER stress in DN presents a potential avenue for therapeutic modulation. Chinese herbal medicine, a staple in Chinese healthcare, has emerged as a promising intervention for DN. Existing research suggests that some herbal remedies may confer renoprotective benefits through the modulation of ER stress. This review explores the involvement of ER stress in the pathogenesis of DN and the advancements in Chinese herbal medicine for ER stress regulation, aiming to inspire new clinical strategies for the prevention and management of DN.
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Affiliation(s)
- Maoying Wei
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xingxing Liu
- Department of Emergency, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingdi Li
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaochan Tian
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingyue Feng
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Boxian Pang
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zeyang Fang
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Department of Endocrinology, Guang’Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Zhang R, Bian C, Gao J, Ren H. Endoplasmic reticulum stress in diabetic kidney disease: adaptation and apoptosis after three UPR pathways. Apoptosis 2023:10.1007/s10495-023-01858-w. [PMID: 37285056 DOI: 10.1007/s10495-023-01858-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2023] [Indexed: 06/08/2023]
Abstract
Diabetes kidney disease (DKD) is one of the common chronic microvascular complications of diabetes, which has become the most important cause of modern chronic kidney disease beyond chronic glomerulonephritis. The endoplasmic reticulum is one of the largest organelles, and endoplasmic reticulum stress (ERS) is the basic mechanism of metabolic disorder in all organs and tissues. Under the stimulation of stress-induced factors, the endoplasmic reticulum, as a trophic receptor, regulates adaptive and apoptotic ERS through molecular chaperones and three unfolded protein reaction (UPR) pathways, thereby regulating diabetic renal damage. Therefore, three pathway factors have different expressions in different sections of renal tissues. This study deeply discussed the specific reagents, animals, cells, and clinical models related to ERS in DKD, and reviewed ERS-related three pathways on DKD with glomerular filtration membrane, renal tubular reabsorption, and other pathological lesions of different renal tissues, as well as the molecular biological mechanisms related to the balance of adaption and apoptosis by searching and sorting out MeSH subject words from PubMed database.
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Affiliation(s)
- Ruijing Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China
| | - Che Bian
- Department of Endocrinology and Metabolism, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jing Gao
- Department of Cardiology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huiwen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China.
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Krishnan S, Manoharan J, Wang H, Gupta D, Fatima S, Yu Y, Mathew A, Li Z, Kohli S, Schwab C, Körner A, Mertens PR, Nawroth P, Shahzad K, Naumann M, Isermann B, Biemann R. CD248 induces a maladaptive unfolded protein response in diabetic kidney disease. Kidney Int 2023; 103:304-319. [PMID: 36309126 DOI: 10.1016/j.kint.2022.09.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 11/06/2022]
Abstract
Dysfunction of mesangial cells plays a major role in the pathogenesis of diabetic kidney disease (DKD), the leading cause of kidney failure. However, the underlying molecular mechanisms are incompletely understood. By unbiased gene expression analysis of glucose-exposed mesangial cells, we identified the transmembrane receptor CD248 as the most upregulated gene, and the maladaptive unfolded protein response (UPR) as one of the most stimulated pathways. Upregulation of CD248 was further confirmed in glucose-stressed mesangial cells in vitro, in kidney glomeruli isolated from diabetic mice (streptozotocin; STZ and db/db models, representing type 1 and type 2 diabetes mellitus, respectively) in vivo, and in glomerular kidney sections from patients with DKD. Time course analysis revealed that glomerular CD248 induction precedes the onset of albuminuria, mesangial matrix expansion and maladaptive UPR activation (hallmarked by transcription factor C/EBP homologous protein (CHOP) induction) but is paralleled by loss of the adaptive UPR regulator spliced X box binding protein (XBP1). Mechanistically, CD248 promoted maladaptive UPR signaling via inhibition of the inositol requiring enzyme 1α (IRE1α)-mediated transcription factor XBP1 splicing in vivo and in vitro. CD248 induced a multiprotein complex comprising heat shock protein 90, BH3 interacting domain death agonist (BID) and IRE1α, in which BID impedes IRE1α-mediated XBP1 splicing and induced CHOP mediated maladaptive UPR signaling. While CD248 knockout ameliorated DKD-associated glomerular dysfunction and reverses maladaptive unfolded protein response signaling, concomitant XBP1 deficiency abolished the protective effect in diabetic CD248 knockout mice, supporting a functional interaction of CD248 and XBP1 in vivo. Hence, CD248 is a novel mesangial cell receptor inducing maladaptive UPR signaling in DKD.
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Affiliation(s)
- Shruthi Krishnan
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Jayakumar Manoharan
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Hongjie Wang
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dheerendra Gupta
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Sameen Fatima
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Yanfei Yu
- Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Akash Mathew
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Zhen Li
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Shrey Kohli
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Constantin Schwab
- Tissue Bank of the National Center for Tumor Diseases, Heidelberg, Germany
| | - Antje Körner
- Leipzig University Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
| | - Peter R Mertens
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Peter Nawroth
- Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany
| | - Khurrum Shahzad
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Ronald Biemann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
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16
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Jin Q, Liu T, Chen D, Yang L, Mao H, Ma F, Wang Y, Li P, Zhan Y. Therapeutic potential of artemisinin and its derivatives in managing kidney diseases. Front Pharmacol 2023; 14:1097206. [PMID: 36874000 PMCID: PMC9974673 DOI: 10.3389/fphar.2023.1097206] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
Artemisinin, an antimalarial traditional Chinese herb, is isolated from Artemisia annua. L, and has shown fewer side effects. Several pieces of evidence have demonstrated that artemisinin and its derivatives exhibited therapeutic effects on diseases like malaria, cancer, immune disorders, and inflammatory diseases. Additionally, the antimalarial drugs demonstrated antioxidant and anti-inflammatory activities, regulating the immune system and autophagy and modulating glycolipid metabolism properties, suggesting an alternative for managing kidney disease. This review assessed the pharmacological activities of artemisinin. It summarized the critical outcomes and probable mechanism of artemisinins in treating kidney diseases, including inflammatory, oxidative stress, autophagy, mitochondrial homeostasis, endoplasmic reticulum stress, glycolipid metabolism, insulin resistance, diabetic nephropathy, lupus nephritis, membranous nephropathy, IgA nephropathy, and acute kidney injury, suggesting the therapeutic potential of artemisinin and its derivatives in managing kidney diseases, especially the podocyte-associated kidney diseases.
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Affiliation(s)
- Qi Jin
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Tongtong Liu
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Danqian Chen
- China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Beijing, China
| | - Liping Yang
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Huimin Mao
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Fang Ma
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Yuyang Wang
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
| | - Ping Li
- China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Beijing, China
| | - Yongli Zhan
- China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, China
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17
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Jeon JH, Im S, Kim HS, Lee D, Jeong K, Ku JM, Nam TG. Chemical Chaperones to Inhibit Endoplasmic Reticulum Stress: Implications in Diseases. Drug Des Devel Ther 2022; 16:4385-4397. [PMID: 36583112 PMCID: PMC9793730 DOI: 10.2147/dddt.s393816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022] Open
Abstract
The endoplasmic reticulum (ER) is responsible for structural transformation or folding of de novo proteins for transport to the Golgi. When the folding capacity of the ER is exceeded or excessive accumulation of misfolded proteins occurs, the ER enters a stressed condition (ER stress) and unfolded protein responses (UPR) are triggered in order to rescue cells from the stress. Recovery of ER proceeds toward either survival or cell apoptosis. ER stress is implicated in many pathologies, such as diabetes, cardiovascular diseases, inflammatory diseases, neurodegeneration, and lysosomal storage diseases. As a survival or adaptation mechanism, chaperone molecules are upregulated to manage ER stress. Chemical versions of chaperone have been developed in search of drug candidates for ER stress-related diseases. In this review, synthetic or semi-synthetic chemical chaperones are categorized according to potential therapeutic area and listed along with their chemical structure and activity. Although only a few chemical chaperones have been approved as pharmaceutical drugs, a dramatic increase in literatures over the recent decades indicates enormous amount of efforts paid by many researchers. The efforts warrant clearer understanding of ER stress and the related diseases and consequently will offer a promising drug discovery platform with chaperone activity.
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Affiliation(s)
- Jae-Ho Jeon
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Gyeonggi-do, 15588, Republic of Korea
| | - Somyoung Im
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Gyeonggi-do, 15588, Republic of Korea
| | - Hyo Shin Kim
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Gyeonggi-do, 15588, Republic of Korea
| | - Dongyun Lee
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Gyeonggi-do, 15588, Republic of Korea
| | - Kwiwan Jeong
- Gyeonggi Bio-Center, Gyeonggido Business and Science Accelerator, Suwon, Gyeonggi-do, 16229, Republic of Korea
| | - Jin-Mo Ku
- Gyeonggi Bio-Center, Gyeonggido Business and Science Accelerator, Suwon, Gyeonggi-do, 16229, Republic of Korea
| | - Tae-Gyu Nam
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Gyeonggi-do, 15588, Republic of Korea,Correspondence: Tae-Gyu Nam, Tel +82-31-400-5807, Fax +82-31-400-5958, Email
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18
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Wang X, Zhao J, Li Y, Rao J, Xu G. Epigenetics and endoplasmic reticulum in podocytopathy during diabetic nephropathy progression. Front Immunol 2022; 13:1090989. [PMID: 36618403 PMCID: PMC9813850 DOI: 10.3389/fimmu.2022.1090989] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
Proteinuria or nephrotic syndrome are symptoms of podocytopathies, kidney diseases caused by direct or indirect podocyte damage. Human health worldwide is threatened by diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD) in the world. DN development and progression are largely dependent on inflammation. The effects of podocyte damage on metabolic disease and inflammatory disorders have been documented. Epigenetic and endoplasmic reticulum (ER) stress are also evident in DN. Targeting inflammation pathway and ER stress in podocytes may be a prospective therapy to prevent the progression of DN. Here, we review the mechanism of epigenetics and ER stress on podocyte inflammation and apoptosis, and discuss the potential amelioration of podocytopathies by regulating epigenetics and ER stress as well as by targeting inflammatory signaling, which provides a theoretical basis for drug development to ameliorate DN.
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Affiliation(s)
- Xiaokang Wang
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China,*Correspondence: Xiaokang Wang,
| | - Jingqian Zhao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Yuanqing Li
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China
| | - Jiaoyu Rao
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China
| | - Gengrui Xu
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, China
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19
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Xie Y, E J, Cai H, Zhong F, Xiao W, Gordon RE, Wang L, Zheng YL, Zhang A, Lee K, He JC. Reticulon-1A mediates diabetic kidney disease progression through endoplasmic reticulum-mitochondrial contacts in tubular epithelial cells. Kidney Int 2022; 102:293-306. [PMID: 35469894 PMCID: PMC9329239 DOI: 10.1016/j.kint.2022.02.038] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 02/18/2022] [Accepted: 02/28/2022] [Indexed: 11/29/2022]
Abstract
Recent epidemiological studies suggest that some patients with diabetes progress to kidney failure without significant albuminuria and glomerular injury, suggesting a critical role of kidney tubular epithelial cell (TEC) injury in diabetic kidney disease (DKD) progression. However, the major risk factors contributing to TEC injury and progression in DKD remain unclear. We previously showed that expression of endoplasmic reticulum-resident protein Reticulon-1A (RTN1A) increased in human DKD, and the increased RTN1A expression promoted TEC injury through endoplasmic reticulum (ER) stress response. Here, we show that TEC-specific RTN1A overexpression worsened DKD in mice, evidenced by enhanced tubular injury, tubulointerstitial fibrosis, and kidney function decline. But RTN1A overexpression did not exacerbate diabetes-induced glomerular injury or albuminuria. Notably, RTN1A overexpression worsened both ER stress and mitochondrial dysfunction in TECs under diabetic conditions by regulation of ER-mitochondria contacts. Mechanistically, ER-bound RTN1A interacted with mitochondrial hexokinase-1 and the voltage-dependent anion channel-1 (VDAC1), interfering with their association. This disengagement of VDAC1 from hexokinase-1 resulted in activation of apoptotic and inflammasome pathways, leading to TEC injury and loss. Thus, our observations highlight the importance of ER-mitochondrial crosstalk in TEC injury and the salient role of RTN1A-mediated ER-mitochondrial contact regulation in DKD progression.
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Affiliation(s)
- Yifan Xie
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jing E
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Nephrology, Ningxia People's Hospital, Ningxia, China
| | - Hong Cai
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fang Zhong
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Wenzhen Xiao
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ronald E Gordon
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Lois Wang
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ya-Li Zheng
- Department of Nephrology, Ningxia People's Hospital, Ningxia, China
| | - Aihua Zhang
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Kyung Lee
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| | - John Cijiang He
- Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Section, James J. Peters Veterans Affair Medical Center, Bronx, New York, USA.
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20
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Demethylation of H3K9 and H3K27 Contributes to the Tubular Renal Damage Triggered by Endoplasmic Reticulum Stress. Antioxidants (Basel) 2022; 11:antiox11071355. [PMID: 35883846 PMCID: PMC9312208 DOI: 10.3390/antiox11071355] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/06/2022] [Accepted: 07/08/2022] [Indexed: 12/10/2022] Open
Abstract
Loss of protein homeostasis (proteostasis) in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), restoring correct protein folding. Sustained ER stress exacerbates activation of the major UPR branches (IRE1α/XBP1, PERK/ATF4, ATF6), inducing expression of numerous genes involved in inflammation, cell death, autophagy, and oxidative stress. We investigated whether epigenetic dynamics mediated by histone H3K9 and H3K27 methylation might help to reduce or inhibit the exacerbated and maladaptive UPR triggered in tubular epithelial cells. Epigenetic treatments, specific silencing, and chromatin immunoprecipitation assays were performed in human proximal tubular cells subjected to ER stress. Pharmacological blockage of KDM4C and JMJD3 histone demethylases with SD-70 and GSKJ4, respectively, enhanced trimethylation of H3K9 and H3K27 in the ATF4 and XBP1 genes, inhibiting their expression and that of downstream genes. Conversely, specific G9a and EZH2 knockdown revealed increases in ATF4 and XBP1 expression. This is a consequence of the reduced recruitment of G9a and EZH2 histone methylases, diminished H3K9me3 and H3K27me3 levels, and enhanced histone acetylation at the ATF4 and XBP1 promoter region. G9a and EZH2 cooperate to maintain the repressive chromatin structure in both UPR-induced genes, ATF4 and XBP1. Therefore, preserving histone H3K9 and H3K27 methylation could ameliorate the ER stress, and consequently the oxidative stress and the triggered pathological processes that aggravate renal damage.
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21
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Wu Y, Yang H, Xu S, Cheng M, Gu J, Zhang W, Liu S, Zhang M. AIM2 inflammasome contributes to aldosterone-induced renal injury via endoplasmic reticulum stress. Clin Sci (Lond) 2022; 136:103-120. [PMID: 34935888 DOI: 10.1042/cs20211075] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/15/2021] [Accepted: 12/22/2021] [Indexed: 11/17/2022]
Abstract
Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental CKD. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and in vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lowered systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor (MR) antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro, while they failed to produce a more remarkable renoprotective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.
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Affiliation(s)
- Yong Wu
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
| | - Huan Yang
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
| | - Sujuan Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Nephrology, Hebei General Hospital, Shijiazhuang, Hebei Province, China
| | - Ming Cheng
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
| | - Jie Gu
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
| | - Weichen Zhang
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
| | - Shaojun Liu
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
| | - Minmin Zhang
- Department of Nephrology, Huashan Hospital and Nephrology Institute, Fudan University, Shanghai, China
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22
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Shahzad K, Fatima S, Al-Dabet MM, Gadi I, Khawaja H, Ambreen S, Elwakiel A, Klöting N, Blüher M, Nawroth PP, Mertens PR, Michel S, Jaschinski F, Klar R, Isermann B. CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease. J Am Soc Nephrol 2021; 32:3066-3079. [PMID: 34479965 PMCID: PMC8638397 DOI: 10.1681/asn.2021040431] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/21/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Maladaptive endoplasmic reticulum stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell-death-promoting transcription factor C/EBP homologous protein (CHOP). Here, we determined whether locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD. METHODS We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study. We used renal functional parameters and morphologic analyses to assess the effect of CHOP-ASO and renal gene-expression profiling to identify differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. RESULTS CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at the early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. CHOP-ASO affected a significantly larger number of genes and disease pathways, including reduced sodium-glucose transport protein 2 (Slc5a2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented death of human kidney cells in vitro . CONCLUSIONS The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi, particularly at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.
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Affiliation(s)
- Khurrum Shahzad
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Sameen Fatima
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany,Institute of Experimental Internal Medicine, Department of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Moh’d Mohanad Al-Dabet
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany,Department of Medical Laboratories, American University of Madaba, Amman, Jordan
| | - Ihsan Gadi
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Hamzah Khawaja
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Saira Ambreen
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Ahmed Elwakiel
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - Nora Klöting
- Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany,Medical Department III, Endocrinology, Nephrology, Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Peter P. Nawroth
- Internal Medicine I and Clinical Chemistry, German Diabetes Center, Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany
| | - Peter R. Mertens
- Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Department of Internal Medicine, Otto-von-Guericke University, Magdeburg, Germany
| | - Sven Michel
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
| | | | - Richard Klar
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Diagnostics, University Hospital Leipzig, Leipzig, Germany
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23
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Carlisle RE, Mohammed-Ali Z, Lu C, Yousof T, Tat V, Nademi S, MacDonald ME, Austin RC, Dickhout JG. TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease. Cell Death Dis 2021; 12:921. [PMID: 34625532 PMCID: PMC8501078 DOI: 10.1038/s41419-021-04197-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/17/2021] [Accepted: 09/08/2021] [Indexed: 12/28/2022]
Abstract
Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-β induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-β receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-β receptor 1, thus, preventing TGF-β-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-β-IRE1-XBP1 pathway.
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Affiliation(s)
- Rachel E Carlisle
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Zahraa Mohammed-Ali
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Chao Lu
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Tamana Yousof
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Victor Tat
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Samera Nademi
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Melissa E MacDonald
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Richard C Austin
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Jeffrey G Dickhout
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada.
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24
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Xu J, Tang Z, He Y, Cai S, Wang B, Zhang S, Wu M, Qian K, Zhang K, Chai B, Chen G, Xu K, Ji H, Xiao J, Wu Y. Dl-3-n-Butylphthalide Ameliorates Diabetic Nephropathy by Ameliorating Excessive Fibrosis and Podocyte Apoptosis. Front Pharmacol 2021; 12:628950. [PMID: 34497508 PMCID: PMC8419457 DOI: 10.3389/fphar.2021.628950] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 08/11/2021] [Indexed: 11/13/2022] Open
Abstract
Diabetic nephropathy (DN) is a common diabetes associated complication. Thus, it is important to understand the pathological mechanism of DN and find the appropriate therapeutic strategy for it. Dl-3-n-Butylphthalide (DL-NBP) has anti-inflammatory and antioxidant effects, and been widely used for the treatment of stroke and cardiovascular diseases. In this study, we selected three different doses (20, 60, and 120 mg⋅kg-1 d-1) of DL-NBP and attempted to elucidate its role and molecular mechanism underlying DN. We found that DL-NBP, especially at the dose of 60 or 120 mg⋅kg-1 d-1, could significantly ameliorate diabetes-induced elevated blood urea nitrogen (BUN) and creatinine level, and alleviate renal fibrosis. Additionally, the elevated expressions of collagen and α-smooth muscle actin (α-SMA) in the kidney from db/db mice were found to be significantly suppressed after DL-NBP treatment. Furthermore, mechanistic studies revealed that DL-NBP inhibits pro-inflammatory cytokine levels, thereby ameliorating the development of renal fibrosis. Moreover, we found that DL-NBP could not only reduce the endoplasmic reticulum stress (ERS), but also suppress activation of the renin-angiotensin system to inhibit vascular endothelial growth factor (VEGF) level, which subsequently reduces the podocyte apoptosis in kidney of db/db mice. In a word, our findings suggest that DL-NBP may be a potential therapeutic drug in the treatment of DN.
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Affiliation(s)
- Jingyu Xu
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Zonghao Tang
- Drug Discovery Research Center, Key Laboratory of Medical Electrophysiology of Ministry of Education, Southwest Medical University, Luzhou, China
| | - Youwu He
- Department of hand and plastic surgery, The First People's Hospital of Yuhang District, Hangzhou, China
| | - Shufang Cai
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Beini Wang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Susu Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Man Wu
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Kai Qian
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Kailun Zhang
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Bo Chai
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Guorong Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ke Xu
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Hao Ji
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Yanqing Wu
- The Institute of Life Sciences, Wenzhou University, Wenzhou, China
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25
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Ma N, Xu N, Yin D, Zheng P, Liu W, Wang G, Hui Y, Han G, Yang C, Cheng X. Levels of circulating GRP78 and CHOP in endoplasmic reticulum stress pathways in Chinese type 2 diabetic kidney disease patients. Medicine (Baltimore) 2021; 100:e26879. [PMID: 34414940 PMCID: PMC8376381 DOI: 10.1097/md.0000000000026879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 07/22/2021] [Indexed: 01/04/2023] Open
Abstract
The current study aimed to investigate circulating glucose-regulated protein 78 (GRP78) as well as CCAAT/enhancer-binding protein homologous protein (CHOP) concentrations in Chinese type 2 diabetes mellitus (T2DM) patients, especially those with microalbuminuria. We recruited 67 patients with T2DM and 63 control subjects. We determined circulating GRP78 and CHOP concentrations by ELISA, collected anthropometric data, and measured biochemical parameters in a clinical laboratory. Compared with control groups, patients with T2DM showed decreased circulating levels of GRP78 (0.21 [0.16-0.24] vs 0.16 [0.16-0.19] ng/mL, P < .01) and CHOP ([0.29 ± 0.02] vs [0.27 ± 0.03]ng/mL, P < .01). Reduction in circulating GRP78 and CHOP levels was more pronounced in patients with more severe categories of albuminuria. Amounts of circulating GRP78 correlated directly with serum fasting c-peptide, cystatin-c (Cys-c), creatinine (Cr), blood urea nitrogen (BUN), and uric acid, and inversely with glomerular filtration rates. Circulating CHOP level was positively correlated with age, Cr, BUN, Cys-c, and urinary microalbumin/creatinine (UmALB/Cr). Circulating GRP78 was predicted independently by Cr, BUN, serum uric acid, estimated glomerular filtration rate, and Cys-c, while CHOP depended on age, Cr, BUN, estimated glomerular filtration rate, UmALB/Cr, and Cys-c. After controlling for confounding factors, circulating GRP78 and CHOP expression were significantly associated with diabetic kidney disease (binary logistic regression, P < .01). Patients with T2DM showed increased circulating GRP78 and CHOP concentrations. Receiver operating characteristic areas under the curve for predicting diabetic kidney disease based on GRP78 and CHOP were 0.686 (95% CI: 0.558-0.813) and 0.670 (0.524-0.816), respectively.
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Affiliation(s)
- Ning Ma
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, China
| | - Ning Xu
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Dong Yin
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Ping Zheng
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Weiwei Liu
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Guofeng Wang
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Yuan Hui
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Guanjun Han
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Chuanhui Yang
- Department of Endocrinology and Metabolism, Lianyungang No1 People's Hospital, 6 Zhenghua Road, Lianyungang, Jiangsu, China
| | - Xingbo Cheng
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, China
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Endoplasmic Reticulum Stress in Diabetic Nephrology: Regulation, Pathological Role, and Therapeutic Potential. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7277966. [PMID: 34394833 PMCID: PMC8355967 DOI: 10.1155/2021/7277966] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/29/2021] [Accepted: 07/17/2021] [Indexed: 12/20/2022]
Abstract
Recent progress has been made in understanding the roles and mechanisms of endoplasmic reticulum (ER) stress in the development and pathogenesis of diabetic nephropathy (DN). Hyperglycemia induces ER stress and apoptosis in renal cells. The induction of ER stress can be cytoprotective or cytotoxic. Experimental treatment of animals with ER stress inhibitors alleviated renal damage. Considering these findings, the normalization of ER stress by pharmacological agents is a promising approach to prevent or arrest DN progression. The current article reviews the mechanisms, roles, and therapeutic aspects of these findings.
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27
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Pradhan LK, Das SK. The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases. Cell Mol Neurobiol 2021; 41:1157-1174. [PMID: 32504327 PMCID: PMC11448699 DOI: 10.1007/s10571-020-00893-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023]
Abstract
In the last few decades, cytoplasmic organellar dysfunction, such as that of the endoplasmic reticulum (ER), has created a new area of research interest towards the development of serious health maladies including neurodegenerative diseases. In this context, the extensively dispersed family of ER-localized proteins, i.e. reticulons (RTNs), is gaining interest because of its regulative control over neural regeneration. As most neurodegenerative diseases are pathologically manifested with the accretion of misfolded proteins with subsequent induction of ER stress, the regulatory role of RTNs in neural dysfunction cannot be ignored. With the limited information available in the literature, delineation of the functional connection between rising consequences of neurodegenerative diseases and RTNs need to be elucidated. In this review, we provide a broad overview on the recently revealed regulatory roles of reticulons in the pathophysiology of several health maladies, with special emphasis on neurodegeneration. Additionally, we have also recapitulated the decisive role of RTN4 in neurite regeneration and highlighted how neurodegeneration and proteinopathies are mechanistically linked with each other through specific RTN paralogues. With the recent findings advocating zebrafish Rtn4b (a mammalian Nogo-A homologue) downregulation following central nervous system (CNS) lesion, RTNs provides new insight into the CNS regeneration. However, there are controversies with respect to the role of Rtn4b in zebrafish CNS regeneration. Given these controversies, the connection between the unique regenerative capabilities of zebrafish CNS by distinct compensatory mechanisms and Rtn4b signalling pathway could shed light on the development of new therapeutic strategies against serious neurodegenerative diseases.
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Affiliation(s)
- Lilesh Kumar Pradhan
- Neurobiology Laboratory, Centre for Biotechnology, Siksha 'O' Anusandhan (Deemed To Be University), Kalinga Nagar, Bhubaneswar, 751003, India
| | - Saroj Kumar Das
- Neurobiology Laboratory, Centre for Biotechnology, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (Deemed To Be University), Kalinga Nagar, Bhubaneswar, 751003, India.
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28
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Meng D, Wu L, Li Z, Ma X, Zhao S, Zhao D, Qin G. LncRNA TUG1 ameliorates diabetic nephropathy via inhibition of PU.1/RTN1 signaling pathway. J Leukoc Biol 2021; 111:553-562. [PMID: 34062006 DOI: 10.1002/jlb.6a1020-699rrr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Diabetic nephropathy (DN) is a leading cause of end-stage renal failure. The study aimed to investigate whether long noncoding RNA taurine-upregulated gene 1 (TUG1) can ameliorate the endoplasmic reticulum stress (ERS) and apoptosis of renal tubular epithelial cells in DN, and the underlying mechanism. The DN mouse model was established by streptozocin injection, and the human renal tubular epithelial cell line HK-2 was treated with high glucose (HG) to mimic DN in vitro. The molecular mechanism was explored through dual-luciferase activity assay, RNA pull-down assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (CHIP) assay. The expression of TUG1 was significantly decreased in the renal tubules of DN model mice. Overexpression of TUG1 reduced the levels of ERS markers and apoptosis markers by inhibiting reticulon-1 (RTN1) expression in HG-induced HK-2 cells. Furthermore, TUG1 down-regulated RTN1 expression by inhibiting the binding of transcription factor PU.1 to the RTN1 promoter, thereby reducing the levels of ERS markers and apoptosis markers. Meanwhile, TUG1-overexpression adenovirus plasmids injection significantly alleviated tubular lesions, and reduced RTN1 expression, ERS markers and apoptosis markers, whereas these results were reversed by injection of PU.1-overexpression adenovirus plasmids. TUG1 restrains the ERS and apoptosis of renal tubular epithelial cells and ameliorates DN through inhibition of transcription factor PU.1.
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Affiliation(s)
- Dongdong Meng
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lina Wu
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhifu Li
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaojun Ma
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuiying Zhao
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Di Zhao
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guijun Qin
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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29
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Yu N, Yang L, Ling L, Liu Y, Yu Y, Wu Q, Gu Y, Niu J. Curcumin attenuates angiotensin II-induced podocyte injury and apoptosis by inhibiting endoplasmic reticulum stress. FEBS Open Bio 2020; 10:1957-1966. [PMID: 32770719 PMCID: PMC7530386 DOI: 10.1002/2211-5463.12946] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/21/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Podocytes are an important component of the glomerular filtration barrier in the kidneys. The dysfunction and apoptosis of podocytes are important factors that can lead to the progression of chronic kidney disease (CKD). In CKD, angiotensin II is continuously elevated in circulation and is considered to have key roles in inducing podocyte injury and apoptosis. Curcumin is a hydrophobic polyphenolic compound extracted from turmeric. Increasing evidence demonstrates that curcumin has a protective effect on the kidneys in CKD. However, the mechanisms mediating this protective effect remain unclear. The aim of this study was to explore whether curcumin could protect against angiotensin II‐induced injury and apoptosis of podocytes. We performed western blotting, immunofluorescence, phalloidin staining, and terminal deoxynucleotidyl transferase nick‐end labeling staining to observe the expression level of podocyte‐specific proteins, apoptosis‐related proteins, and the arrangement of F‐actin. We found that curcumin could reverse angiotensin II‐induced podocyte injury and apoptosis in a dose‐dependent manner. In addition, curcumin dose‐dependently attenuated a pro‐apoptotic pathway, activated by angiotensin II‐induced endoplasmic reticulum stress. Conversely, the protective effects of curcumin were impaired upon addition of tunicamycin, an activator of endoplasmic reticulum stress. Thus, we speculate that curcumin protects against angiotensin II‐induced podocyte injury and apoptosis, at least partly by inhibiting endoplasmic reticulum stress.
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Affiliation(s)
- Nan Yu
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Lin Yang
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Lilu Ling
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Yuan Liu
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Ying Yu
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Qing Wu
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Yong Gu
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.,Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jianying Niu
- Department of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
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30
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Huang FC, Hwang HH. Arabidopsis RETICULON-LIKE4 (RTNLB4) Protein Participates in Agrobacterium Infection and VirB2 Peptide-Induced Plant Defense Response. Int J Mol Sci 2020; 21:ijms21051722. [PMID: 32138311 PMCID: PMC7084338 DOI: 10.3390/ijms21051722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/28/2020] [Accepted: 02/29/2020] [Indexed: 12/27/2022] Open
Abstract
Agrobacterium tumefaciens uses the type IV secretion system, which consists of VirB1-B11 and VirD4 proteins, to deliver effectors into plant cells. The effectors manipulate plant proteins to assist in T-DNA transfer, integration, and expression in plant cells. The Arabidopsis reticulon-like (RTNLB) proteins are located in the endoplasmic reticulum and are involved in endomembrane trafficking in plant cells. The rtnlb4 mutants were recalcitrant to A. tumefaciens infection, but overexpression of RTNLB4 in transgenic plants resulted in hypersusceptibility to A. tumefaciens transformation, which suggests the involvement of RTNLB4 in A. tumefaciens infection. The expression of defense-related genes, including FRK1, PR1, WRKY22, and WRKY29, were less induced in RTNLB4 overexpression (O/E) transgenic plants after A. tumefaciens elf18 peptide treatment. Pretreatment with elf18 peptide decreased Agrobacterium-mediated transient expression efficiency more in wild-type seedlings than RTNLB4 O/E transgenic plants, which suggests that the induced defense responses in RTNLB4 O/E transgenic plants might be affected after bacterial elicitor treatments. Similarly, A. tumefaciens VirB2 peptide pretreatment reduced transient T-DNA expression in wild-type seedlings to a greater extent than in RTNLB4 O/E transgenic seedlings. Furthermore, the VirB2 peptides induced FRK1, WRKY22, and WRKY29 gene expression in wild-type seedlings but not efr-1 and bak1 mutants. The induced defense-related gene expression was lower in RTNLB4 O/E transgenic plants than wild-type seedlings after VirB2 peptide treatment. These data suggest that RTNLB4 may participate in elf18 and VirB2 peptide-induced defense responses and may therefore affect the A. tumefaciens infection process.
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Affiliation(s)
- Fan-Chen Huang
- Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan;
- Ph.D. Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taichung 402, Taiwan
| | - Hau-Hsuan Hwang
- Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan;
- Ph.D. Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taichung 402, Taiwan
- Innovation and Development Center of Sustainable Agriculture, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: ; Tel.: +886-4-2284-0416-412
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31
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Zhang X, Ding X, Marshall RS, Paez-Valencia J, Lacey P, Vierstra RD, Otegui MS. Reticulon proteins modulate autophagy of the endoplasmic reticulum in maize endosperm. eLife 2020; 9:51918. [PMID: 32011236 PMCID: PMC7046470 DOI: 10.7554/elife.51918] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 02/02/2020] [Indexed: 12/18/2022] Open
Abstract
Reticulon (Rtn) proteins shape tubular domains of the endoplasmic reticulum (ER), and in some cases are autophagy receptors for selective ER turnover. We have found that maize Rtn1 and Rtn2 control ER homeostasis and autophagic flux in endosperm aleurone cells, where the ER accumulates lipid droplets and synthesizes storage protein accretions metabolized during germination. Maize Rtn1 and Rtn2 are expressed in the endosperm, localize to the ER, and re-model ER architecture in a dose-dependent manner. Rtn1 and Rtn2 interact with Atg8a using four Atg8-interacting motifs (AIMs) located at the C-terminus, cytoplasmic loop, and within the transmembrane segments. Binding between Rtn2 and Atg8 is elevated upon ER stress. Maize rtn2 mutants display increased autophagy and up-regulation of an ER stress-responsive chaperone. We propose that maize Rtn1 and Rtn2 act as receptors for autophagy-mediated ER turnover, and thus are critical for ER homeostasis and suppression of ER stress.
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Affiliation(s)
- Xiaoguo Zhang
- Department of Botany, Laboratory of Cell and Molecular Biology, University of Wisconsin, Madison, United States
| | - Xinxin Ding
- Department of Botany, Laboratory of Cell and Molecular Biology, University of Wisconsin, Madison, United States
| | | | - Julio Paez-Valencia
- Department of Botany, Laboratory of Cell and Molecular Biology, University of Wisconsin, Madison, United States
| | - Patrick Lacey
- Department of Botany, Laboratory of Cell and Molecular Biology, University of Wisconsin, Madison, United States
| | | | - Marisa S Otegui
- Department of Botany, Laboratory of Cell and Molecular Biology, University of Wisconsin, Madison, United States.,Department of Genetics, University of Wisconsin, Madison, United States
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32
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Sankrityayan H, Oza MJ, Kulkarni YA, Mulay SR, Gaikwad AB. ER stress response mediates diabetic microvascular complications. Drug Discov Today 2019; 24:2247-2257. [PMID: 31430543 DOI: 10.1016/j.drudis.2019.08.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/19/2019] [Accepted: 08/01/2019] [Indexed: 12/16/2022]
Abstract
Endoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS.
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Affiliation(s)
- Himanshu Sankrityayan
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India
| | - Manisha J Oza
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India; SVKM's Dr Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India
| | - Shrikant R Mulay
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
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Shibusawa R, Yamada E, Okada S, Nakajima Y, Bastie CC, Maeshima A, Kaira K, Yamada M. Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death. Sci Rep 2019; 9:9887. [PMID: 31285506 PMCID: PMC6614429 DOI: 10.1038/s41598-019-46402-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 06/26/2019] [Indexed: 01/14/2023] Open
Abstract
The new type 2 diabetes drug, dapagliflozin, reduces blood glucose levels and body weight by inhibiting sodium glucose transporter 2 (SGLT2) in proximal tubular cells. SGLT2 inhibitors might modulate glucose influx into renal tubular cells, thereby regulating the metabolic conditions that cause endoplasmic reticulum (ER) stress in the cells. In this study, we examined the effect of dapagliflozin on ER stress in the HK-2 proximal tubular cell line and in the kidney of db/db mice to characterise its function in diabetic nephropathy (DN). We found that dapagliflozin regulated ER stress-mediated apoptosis in vitro and in vivo. Only the elf2α-ATF4-CHOP pathway was regulated under these conditions. Notably, the drug rescued C2 ceramide-induced ER stress-mediated apoptosis and ER stress-mediated apoptosis, which might occur in DN, in db/db mice. Our study shows a novel role for dapagliflozin as an inhibitor of ER stress and suggests that dapagliflozin might be useful for the prevention of DN.
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Affiliation(s)
- Ryo Shibusawa
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan
| | - Eijiro Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.
| | - Shuichi Okada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan
| | - Yasuyo Nakajima
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan
| | - Claire C Bastie
- Division of Biomedical Sciences, Warwick Medical School, Coventry, West Midlands, United Kingdom
| | - Akito Maeshima
- Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigii, Japan
| | - Kyoichi Kaira
- Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan
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34
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Mathematical model of hemodynamic mechanisms and consequences of glomerular hypertension in diabetic mice. NPJ Syst Biol Appl 2018; 5:2. [PMID: 30564457 PMCID: PMC6288095 DOI: 10.1038/s41540-018-0077-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 06/29/2018] [Accepted: 10/22/2018] [Indexed: 12/12/2022] Open
Abstract
Many preclinically promising therapies for diabetic kidney disease fail to provide efficacy in humans, reflecting limited quantitative translational understanding between rodent models and human disease. To quantitatively bridge interspecies differences, we adapted a mathematical model of renal function from human to mice, and incorporated adaptive and pathological mechanisms of diabetes and nephrectomy to describe experimentally observed changes in glomerular filtration rate (GFR) and proteinuria in db/db and db/db UNX (uninephrectomy) mouse models. Changing a small number of parameters, the model reproduced interspecies differences in renal function. Accounting for glucose and Na+ reabsorption through sodium glucose cotransporter 2 (SGLT2), increasing blood glucose and Na+ intake from normal to db/db levels mathematically reproduced glomerular hyperfiltration observed experimentally in db/db mice. This resulted from increased proximal tubule sodium reabsorption, which elevated glomerular capillary hydrostatic pressure (Pgc) in order to restore sodium balance through increased GFR. Incorporating adaptive and injurious effects of elevated Pgc, we showed that preglomerular arteriole hypertrophy allowed more direct transmission of pressure to the glomerulus with a smaller mean arterial pressure rise; Glomerular hypertrophy allowed a higher GFR for a given Pgc; and Pgc-driven glomerulosclerosis and nephron loss reduced GFR over time, while further increasing Pgc and causing moderate proteinuria, in agreement with experimental data. UNX imposed on diabetes increased Pgc further, causing faster GFR decline and extensive proteinuria, also in agreement with experimental data. The model provides a mechanistic explanation for hyperfiltration and proteinuria progression that will facilitate translation of efficacy for novel therapies from mouse models to human. Many drugs for diabetic kidney disease appear to work in rodents, but fail in humans, reflecting incomplete understanding of disease processes. A team led by Melissa Hallow at the University of Georgia has developed a mathematical model that explains how elevated blood glucose in diabetes causes kidney injury in mice. They first showed that normal human, rat, or mouse kidney physiology could be reproduced with the same model by changing a small number of parameters. They then showed that diabetes-induced increases in sodium reabsorption cause unintuitive changes in kidney function that increase pressure on glomerular capillaries, causing protein leakage and nephron loss. The model reproduced faster disease progression observed in diabetic mice who have had one kidney removed. This mathematical understanding of diabetic kidney injury may improve translation of novel therapies from mice to human.
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35
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Lu XY, Zhou FH, Dong YQ, Gong LN, Li QY, Tang L, Cai Z, He JY, Liu MH. Codonopsis tangshen Oliv. Amelioration Effect on Diabetic Kidney Disease Rats Induced by High Fat Diet Feeding Combined with Streptozotocin. NATURAL PRODUCTS AND BIOPROSPECTING 2018; 8:441-451. [PMID: 30387083 PMCID: PMC6224812 DOI: 10.1007/s13659-018-0187-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 10/15/2018] [Indexed: 05/04/2023]
Abstract
Diabetic kidney disease (DKD) is the most serious microvascular complication during the development of diabetes with the characterizations of glomerular basement membrane thickening, mesangial expansion, and glomerular sclerosis, eventually leading to end-stage renal disease. This study aimed to investigate the melioration effect of Codonopisis tangshen Oliv. (COD) on the DKD model, which was established by unilateral nephrectomy (UN)-high fat diet feeding (HFD) combined with streptozotocin (STZ). After the DKD rats were oral treated with COD at a dose of 2.7 mg/kg for 4 consecutive weeks, the blood glucose, lipid metabolism, renal function, inflammatory mediators, and fibrosis-associated proteins were examined. In vivo, the COD administration obviously relieved the weight loss, water intake, and blood glucose; decreased the total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels; and improved the renal function by reducing the expression of serum creatinine, uric acid, and urinary protein compared with the model group. The levels of pro-inflammatory cytokines of tumor necrosis factor-α, interleukin-1β, and IL-6 were significantly inhibited by COD. Meanwhile, the deposition of collagen fiber was markedly increased, and the protein and mRNA expressions of transforming growth factor-β1 and α-smooth muscle actin were markedly elevated in DKD rats, but they were decreased to some extent after the COD treatment. In conclusion, COD exhibited a protective effect on the UN-HFD feeding combined with STZ-induced DKD model by improving the blood glucose and lipid metabolism, relieving the inflammatory response, and mitigating the renal fibrosis, which provided scientific evidence for its applications in clinic.
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Affiliation(s)
- Xian-Yuan Lu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Feng-Hua Zhou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515 China
| | - Ya-Qian Dong
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Lin-Na Gong
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Qing-Yun Li
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Lan Tang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Zheng Cai
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
| | - Jing-Yu He
- Bioengineering Research Centre, Guangzhou Institute of Advanced Technology, Chinese Academy of Sciences, Guangzhou, 511458 China
| | - Meng-Hua Liu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
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36
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Feng Q, Wang H, Pang J, Ji L, Han J, Wang Y, Qi X, Liu Z, Lu L. Prevention of Wogonin on Colorectal Cancer Tumorigenesis by Regulating p53 Nuclear Translocation. Front Pharmacol 2018; 9:1356. [PMID: 30532707 PMCID: PMC6265339 DOI: 10.3389/fphar.2018.01356] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 11/05/2018] [Indexed: 01/10/2023] Open
Abstract
The tumor suppressor protein p53 plays an important role in the development and progression of colon cancer, and the subcellular organelle localization directly affects its function. Wogonin (5,7-dihydroxy-8-methoxyflavone), a mono-flavonoid extracted from root of Scutellaria baicalensis Georgi, possesses acceptable toxicity and has been used in colorectal cancer (CRC) chemoprevention in pre-clinical trials by oncologist. However, the underlying anti-colon cancer mechanisms of wogonin are not yet fully understood. In the present study, the effect of wogonin on the initiation and development of colitis-associated cancer through p53 nuclear translocation was explored. AOM-DSS CRC animal model and human CRC HCT-116 cell model were used to evaluate the in vivo and in vitro anti-colon cancer action of wogonin. We observed that wogonin showed a dramaticlly preventive effect on colon cancer. Our results showed that wogonin caused apoptotic cell death in human CRC HCT-116 cell through increased endoplasmic reticulum (ER) stress. Meanwhile, excessive ER stress facilitated the cytoplasmic localization of p53 through increasing phosphor-p53 at S315 and S376 sites, induced caspase-dependent apoptosis and inhibited autophagy. Furthermore, we verified the chemoprevention effect and toxicity of wogonin in vivo by utilizing an AOM-DSS colon cancer animal model. We found that wogonin not only reduced tumor multiplicity, preserved colon length to normal (6.79 ± 0.34 to 7.41 ± 0.56, P < 0.05) but also didn’t induce side effects on various organs. In conclusion, these results explain the anti-tumor effect of wogonin in CRC and suggest wogonin as a potential therapeutic candidate for the therapeutic strategy in CRC treatment.
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Affiliation(s)
- Qian Feng
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,The Postdoctoral Research Station, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haojia Wang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaying Pang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liyan Ji
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiada Han
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Wang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoxiao Qi
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhongqiu Liu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linlin Lu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Pandey VK, Mathur A, Kakkar P. Emerging role of Unfolded Protein Response (UPR) mediated proteotoxic apoptosis in diabetes. Life Sci 2018; 216:246-258. [PMID: 30471281 DOI: 10.1016/j.lfs.2018.11.041] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/16/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023]
Abstract
Endoplasmic reticulum (ER) is a crucial single membrane organelle that acts as a quality control system for cellular proteins as it is intricately involved in their synthesis, folding and trafficking to the respective targets. Type 2 diabetes is characterized by enhanced blood glucose level that promotes insulin resistance and hampers cellular glucose metabolism. Hyperglycemia provokes mitochondrial ROS production and glycation of proteins which exert a tremendous load on ER for conventional refolding of misfolded/unfolded and nascent proteins that perturb ER homeostasis resulting in apoptotic cell death. Impairment in ER functions is suspected to be through specific ER membrane-bound proteins known as Unfolded Protein Response (UPR) sensor proteins. Conformational changes in these proteins induce oligomerization and cross-autophosphorylation which facilitate processes required for the restoration of ER homeostatic imbalance. Multiple studies have reported the involvement of UPR mediated autophagy and apoptotic pathways in the progression of metabolic disorders including diabetes, cardiac ischemia/reperfusion injury and hypoxia-mediated cell death. In this review, the involvement of UPR pathways in the progression of diabetes associated complications have been addressed, which underscores molecular crosstalks during neuropathy, nephropathy, hepatic injury and retinopathy. A better understanding of these molecular interventions may reveal advanced therapeutic approaches for preventing diabetic comorbidities. The article also highlights the importance of phytochemicals that are emerging as novel ER stress inhibitors and are being explored for targeted interaction in preventing cell death responses during diabetes.
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Affiliation(s)
- Vivek Kumar Pandey
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan 31, M.G Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India
| | - Alpana Mathur
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan 31, M.G Marg, Lucknow 226001, Uttar Pradesh, India; Babu Banarasi Das University, Lucknow, Uttar Pradesh, India
| | - Poonam Kakkar
- Herbal Research Laboratory, Food, Drug & Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan 31, M.G Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India.
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38
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Tian N, Gao Y, Wang X, Wu X, Zou D, Zhu Z, Han Z, Wang T, Shi Y. Emodin mitigates podocytes apoptosis induced by endoplasmic reticulum stress through the inhibition of the PERK pathway in diabetic nephropathy. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:2195-2211. [PMID: 30034224 PMCID: PMC6047613 DOI: 10.2147/dddt.s167405] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown. Aim This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK–eIF2α pathway. Methods KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro. Results The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP. Conclusion Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN.
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Affiliation(s)
- Nianxiu Tian
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China,
| | - Yanbin Gao
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China,
| | - Xiaolei Wang
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China,
| | - Xiaoming Wu
- Department of Paediatrics, Beijing Children's Hospital, Capital Medical University, Xicheng District, Beijing, China
| | - Dawei Zou
- Department of Endocrinology, Beijing Key Lab of TCM Collateral Disease theory Research, Fengtai District, Beijing, China
| | - Zhiyao Zhu
- Department of Endocrinology, Beijing Key Lab of TCM Collateral Disease theory Research, Fengtai District, Beijing, China
| | - ZheJi Han
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China,
| | - Tao Wang
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China,
| | - Yimin Shi
- Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China,
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Li Y, Zhong Y, Gong W, Gao X, Qi H, Liu K, Qi J. C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis. J Mol Endocrinol 2018; 61:47-56. [PMID: 29844093 DOI: 10.1530/jme-18-0009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 05/02/2018] [Indexed: 12/17/2022]
Abstract
Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains (Col4a1-a5), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism. Col4a1-a5 expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters of Col4a1a2, Col4a3a4 and Col4a5 were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renal Col4a1-a5 mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibit Col4a1-a5 mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide.
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Affiliation(s)
- Yanning Li
- Department of Molecular BiologyHebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, China
| | - Yan Zhong
- Department of BiochemistryHebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Wenjian Gong
- Department of Molecular BiologyHebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, China
| | - Xuehan Gao
- Department of Molecular BiologyHebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, China
| | - Huanli Qi
- Department of BiochemistryHebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Kun Liu
- Department of BiochemistryHebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Jinsheng Qi
- Department of BiochemistryHebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
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40
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Pardue MT, Allen RS. Neuroprotective strategies for retinal disease. Prog Retin Eye Res 2018; 65:50-76. [PMID: 29481975 PMCID: PMC6081194 DOI: 10.1016/j.preteyeres.2018.02.002] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 02/14/2018] [Accepted: 02/20/2018] [Indexed: 12/20/2022]
Abstract
Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.
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Affiliation(s)
- Machelle T Pardue
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA, 30033, USA; Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA.
| | - Rachael S Allen
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA, 30033, USA
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41
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Kropski JA, Blackwell TS. Endoplasmic reticulum stress in the pathogenesis of fibrotic disease. J Clin Invest 2018; 128:64-73. [PMID: 29293089 DOI: 10.1172/jci93560] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Eukaryotic cells contain an elegant protein quality control system that is crucial in maintaining cellular homeostasis; however, dysfunction of this system results in endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Severe or prolonged ER stress is associated with the development of degenerative and fibrotic disorders in multiple organs, as evidenced by the identification of disease-causing mutations in epithelial-restricted genes that lead to protein misfolding or mistrafficking in familial fibrotic diseases. Emerging evidence implicates ER stress and UPR signaling in a variety of profibrotic mechanisms in individual cell types. In epithelial cells, ER stress can induce apoptosis, inflammatory signaling, and epithelial-mesenchymal transition. In other cell types, ER stress is linked to myofibroblast activation, macrophage polarization, and T cell differentiation. ER stress-targeted therapies have begun to emerge using approaches that range from global enhancement of chaperone function to selective targeting of activated ER stress sensors and other downstream mediators. As the complex regulatory mechanisms of this system are further clarified, there are opportunities to develop new disease-modifying therapeutic strategies in a wide range of chronic fibrotic diseases.
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Affiliation(s)
- Jonathan A Kropski
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA
| | - Timothy S Blackwell
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA.,Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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42
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He L, Fan Y, Xiao W, Chen T, Wen J, Dong Y, Wang Y, Li S, Xue R, Zheng L, He JC, Wang N. Febuxostat attenuates ER stress mediated kidney injury in a rat model of hyperuricemic nephropathy. Oncotarget 2017; 8:111295-111308. [PMID: 29340054 PMCID: PMC5762322 DOI: 10.18632/oncotarget.22784] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 11/16/2017] [Indexed: 02/07/2023] Open
Abstract
Hyperuricemia contributes to kidney tubular injury and kidney fibrosis. However, the underlying mechanism remains unclear. Here we examined the role of RTN1A, a novel endoplasmic reticulum (ER)-associated protein and ER stress in hyperuricemic nephropathy. We first found the expression of RTN1A and ER stress markers was significantly increased in kidney biopsies of hyperuricemia patients with kidney injury. In a rat model of hyperuricemic nephropathy (HN) established by oral administration of a mixture of adenine and potassium oxonate, increased expression of RTN1A and ER stress was shown in tubular and interstitial compartment of rat kidneys. Treatment of Febuxostat, a new selective inhibitor of xanthine oxidase (XO), not only attenuated renal tubular injury and tubulointerstitial fibrosis, but also reduced uric acid crystals deposition in HN rat kidneys. In vitro, Febuxostat also reduced ER stress and apoptosis in uric acid treated tubular epithelial cells. Our data suggest that RTN1A and ER stress mediate tubular cell injury and kidney fibrosis in HN. Urate-lowering therapy (ULT) with Febuxostat attenuates uric-acid induced ER stress in renal tubular cells and the progression of HN.
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Affiliation(s)
- Li He
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ying Fan
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wenzhen Xiao
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Teng Chen
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jiejun Wen
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yang Dong
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yiyun Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Shiqi Li
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Rui Xue
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Liyang Zheng
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - John Cijiang He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Niansong Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Lindholm D, Korhonen L, Eriksson O, Kõks S. Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease. Front Cell Dev Biol 2017; 5:48. [PMID: 28540288 PMCID: PMC5423914 DOI: 10.3389/fcell.2017.00048] [Citation(s) in RCA: 149] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/13/2017] [Indexed: 12/20/2022] Open
Abstract
Unfolded stress response (UPR) is a conserved cellular pathway involved in protein quality control to maintain homeostasis under different conditions and disease states characterized by cell stress. Although three general schemes of and genes induced by UPR are rather well-established, open questions remain including the precise role of UPR in human diseases and the interactions between different sensor systems during cell stress signaling. Particularly, the issue how the normally adaptive and pro-survival UPR pathway turns into a deleterious process causing sustained endoplasmic reticulum (ER) stress and cell death requires more studies. UPR is also named a friend with multiple personalities that we need to understand better to fully recognize its role in normal physiology and in disease pathology. UPR interacts with other organelles including mitochondria, and with cell stress signals and degradation pathways such as autophagy and the ubiquitin proteasome system. Here we review current concepts and mechanisms of UPR as studied in different cells and model systems and highlight the relevance of UPR and related stress signals in various human diseases.
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Affiliation(s)
- Dan Lindholm
- Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of HelsinkiHelsinki, Finland.,Minerva Foundation Institute for Medical ResearchHelsinki, Finland
| | - Laura Korhonen
- Minerva Foundation Institute for Medical ResearchHelsinki, Finland.,Division of Child Psychiatry, Helsinki University Central HospitalHelsinki, Finland
| | - Ove Eriksson
- Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of HelsinkiHelsinki, Finland
| | - Sulev Kõks
- Department of Pathophysiology, University of TartuTartu, Estonia.,Department of Reproductive Biology, Estonian University of Life SciencesTartu, Estonia
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