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Fu L, Yokus B, Gao B, Pacher P. An update on IL-22 therapies in alcohol-associated liver disease and beyond. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00117-8. [PMID: 40254130 DOI: 10.1016/j.ajpath.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/14/2025] [Accepted: 03/21/2025] [Indexed: 04/22/2025]
Abstract
Excessive alcohol consumption drives the development of alcohol-associated liver disease (ALD), including steatohepatitis, cirrhosis, and hepatocellular carcinoma, and its associated complications, such as hepatorenal syndrome. Hepatocyte death, inflammation, and impaired liver regeneration are key processes implicated in the pathogenesis and progression of ALD. Despite extensive research, therapeutic options for ALD remain limited. Interleukin-22 (IL-22) has emerged as a promising therapeutic target due to its hepatoprotective properties mediated through the activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway. IL-22 enhances hepatocyte survival by mitigating apoptosis, oxidative stress, and inflammation while simultaneously promoting liver regeneration through the proliferation of hepatocytes and hepatic progenitor cells and the upregulation of growth factors. Additionally, IL-22 exerts protective effects on epithelial cells in various organs affected by ALD and its associated complications. Studies from preclinical models and early-phase clinical trials of IL-22 agonists, such as F-652 and UTTR1147A, have shown favorable safety profiles, good tolerability, and encouraging efficacy in reducing liver injury and promoting regeneration. However, the heterogeneity and multifactorial nature of ALD present ongoing challenges. Further research is needed to optimize IL-22-based therapies and clarify their roles within a comprehensive approach to ALD management. This review summarizes the current understanding of IL-22 biology and its role in ALD pathophysiology and ALD-associated complications along with therapeutic application of IL-22, potential benefits and limitations.
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Affiliation(s)
- Lihong Fu
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA
| | - Burhan Yokus
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institutes of Health/NIAAA.
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA.
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2
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Baker ML, Cantley LG. Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury. J Clin Invest 2025; 135:e188358. [PMID: 40091836 PMCID: PMC11910233 DOI: 10.1172/jci188358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
Acute kidney injury (AKI) encompasses pathophysiology ranging from glomerular hypofiltration to tubular cell injury and outflow obstruction. This Review will focus on the tubulointerstitial processes that underlie most cases of AKI. Tubular epithelial cell (TEC) injury can occur via distinct insults, including ischemia, nephrotoxins, sepsis, and primary immune-mediated processes. Following these initial insults, tubular cells can activate survival and repair responses or they can develop mitochondrial dysfunction and metabolic reprogramming, cell-cycle arrest, and programmed cell death. Developing evidence suggests that the fate of individual tubular cells to survive and proliferate or undergo cell death or senescence is frequently determined by a biphasic immune response with initial proinflammatory macrophage, neutrophil, and lymphocyte infiltration exacerbating injury and activating programmed cell death, while alternatively activated macrophages and specific lymphocyte subsets subsequently modulate inflammation and promote repair. Functional recovery requires that this reparative phase supports proteolytic degradation of tubular casts, proliferation of surviving TECs, and restoration of TEC differentiation. Incomplete resolution or persistence of inflammation can lead to failed tubular repair, fibrosis, and chronic kidney disease. Despite extensive research in animal models, translating preclinical findings to therapies remains challenging, emphasizing the need for integrated multiomic approaches to advance AKI understanding and treatment.
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Kurts C, von Vietinghoff S, Krebs CF, Panzer U. Kidney immunology from pathophysiology to clinical translation. Nat Rev Immunol 2025:10.1038/s41577-025-01131-y. [PMID: 39885266 DOI: 10.1038/s41577-025-01131-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/02/2025] [Indexed: 02/01/2025]
Abstract
Kidney diseases are widespread and represent a considerable medical, social and economic burden. However, there has been marked progress in understanding the immunological aspects of kidney disease. This includes the identification of distinct intrarenal immunological niches and characterization of kidney disease endotypes according to the underlying molecular immunopathology, as well as a better understanding of the pathological roles for T cells, mononuclear phagocytes and B cells and the renal elements they target. These insights have improved the diagnosis of kidney disease. Here, we discuss new developments in our understanding of kidney immunology, focusing on immune mechanisms of disease and their translational implications for the diagnosis and treatment of kidney disease. We also describe the immune-mediated crosstalk between the kidney and other organs that influences kidney disease and extrarenal inflammation.
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Affiliation(s)
- Christian Kurts
- Institute of Molecular Medicine and Experimental Immunology, University Hospital, Bonn, Germany.
- Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
| | - Sibylle von Vietinghoff
- Nephrology Section, University Hospital Bonn, Medical Clinic and Polyclinic I, Bonn, Germany
| | - Christian F Krebs
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulf Panzer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Lee K, Jang HR, Rabb H. Lymphocytes and innate immune cells in acute kidney injury and repair. Nat Rev Nephrol 2024; 20:789-805. [PMID: 39095505 DOI: 10.1038/s41581-024-00875-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 08/04/2024]
Abstract
Acute kidney injury (AKI) is a common and serious disease entity that affects native kidneys and allografts but for which no specific treatments exist. Complex intrarenal inflammatory processes driven by lymphocytes and innate immune cells have key roles in the development and progression of AKI. Many studies have focused on prevention of early injury in AKI. However, most patients with AKI present after injury is already established. Increasing research is therefore focusing on mechanisms of renal repair following AKI and prevention of progression from AKI to chronic kidney disease. CD4+ and CD8+ T cells, B cells and neutrophils are probably involved in the development and progression of AKI, whereas regulatory T cells, double-negative T cells and type 2 innate lymphoid cells have protective roles. Several immune cells, such as macrophages and natural killer T cells, can have both deleterious and protective effects, depending on their subtype and/or the stage of AKI. The immune system not only participates in injury and repair processes during AKI but also has a role in mediating AKI-induced distant organ dysfunction. Targeted manipulation of immune cells is a promising therapeutic strategy to improve AKI outcomes.
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Affiliation(s)
- Kyungho Lee
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Cell and Gene Therapy Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hye Ryoun Jang
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Cell and Gene Therapy Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hamid Rabb
- Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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5
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Liu C, Wei W, Huang Y, Fu P, Zhang L, Zhao Y. Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications. Metabolism 2024; 158:155974. [PMID: 38996912 DOI: 10.1016/j.metabol.2024.155974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/06/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
Acute kidney injury (AKI) is a frequent and severe complication of sepsis and is characterized by significant mortality and morbidity. However, the pathogenesis of septic acute kidney injury (S-AKI) remains elusive. Metabolic reprogramming, which was originally referred to as the Warburg effect in cancer, is strongly related to S-AKI. At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli. As the disease progresses, these cells revert to oxidative phosphorylation, thus promoting anti-inflammatory reactions and enhancing functional restoration. Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during S-AKI. In this review, we summarize the current understanding of the pathogenesis of metabolic reprogramming in S-AKI, with a focus on each cell type involved. By identifying relevant key regulatory factors, we also explored potential metabolic reprogramming-related therapeutic targets for the management of S-AKI.
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Affiliation(s)
- Caihong Liu
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Wei Wei
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yongxiu Huang
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ping Fu
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ling Zhang
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yuliang Zhao
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
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Zhang D, Jiang H, Yang X, Zheng S, Li Y, Liu S, Xu X. Traditional Chinese Medicine and renal regeneration: experimental evidence and future perspectives. Chin Med 2024; 19:77. [PMID: 38831435 PMCID: PMC11149241 DOI: 10.1186/s13020-024-00935-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 06/05/2024] Open
Abstract
Repair of acute kidney injury (AKI) is a typical example of renal regeneration. AKI is characterized by tubular cell death, peritubular capillary (PTC) thinning, and immune system activation. After renal tubule injury, resident renal progenitor cells, or renal tubule dedifferentiation, give rise to renal progenitor cells and repair the damaged renal tubule through proliferation and differentiation. Mesenchymal stem cells (MSCs) also play an important role in renal tubular repair. AKI leads to sparse PTC, affecting the supply of nutrients and oxygen and indirectly aggravating AKI. Therefore, repairing PTC is important for the prognosis of AKI. The activation of the immune system is conducive for the body to clear the necrotic cells and debris generated by AKI; however, if the immune activation is too strong or lengthy, it will cause damage to renal tubule cells or inhibit their repair. Macrophages have been shown to play an important role in the repair of kidney injury. Traditional Chinese medicine (TCM) has unique advantages in the treatment of AKI and a series of studies have been conducted on the topic in recent years. Herein, the role of TCM in promoting the repair of renal injury and its molecular mechanism is discussed from three perspectives: repair of renal tubular epithelial cells, repair of PTC, and regulation of macrophages to provide a reference for the treatment and mechanistic research of AKI.
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Affiliation(s)
- Denglu Zhang
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huihui Jiang
- Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xianzhen Yang
- Urinary Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Sanxia Zheng
- Pediatric Department, The Second Affiliated Hospital of Shandong University of Chinese Medicine, Jinan, China
| | - Yi Li
- Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Shuai Liu
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Xiangdong Xu
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
- Shandong Key Laboratory of Dominant Diseases of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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Wang Q, Wang F, Zhou Y, Li X, Xu S, Jin Q, Li W. Bacillus amyloliquefaciens SC06 Relieving Intestinal Inflammation by Modulating Intestinal Stem Cells Proliferation and Differentiation via AhR/STAT3 Pathway in LPS-Challenged Piglets. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:6096-6109. [PMID: 38484112 DOI: 10.1021/acs.jafc.3c05956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Bacillus amyloliquefaciens is a well-accepted probiotic, with many benefits for both humans and animals. The ability of intestinal stem cells (ISCs) to develop into several intestinal epithelial cell types helps accelerate intestinal epithelial regeneration. Limited knowledge exists on how bacteria regulated ISCs proliferation and regeneration. Our study investigated the effects of Bacillus amyloliquefaciens supplementation on ISC proliferation and regeneration and intestinal mucosal barrier functions in piglets exposed to lipopolysaccharide (LPS). Eighteen piglets (male, 21 days old) were randomly split into 3 clusters: CON cluster, LPS cluster, and SC06+LPS cluster. On day 21, 100 μg/kg body weight of LPS was intraperitoneally administered to the SC06+LPS and LPS groups. We found SC06 supplementation maintained the intestinal barrier integrity, enhanced intestinal antioxidant capacity, reduced generation of inflammatory response, and suppressed enterocyte apoptosis against the deleterious effects triggered by LPS. In addition, our research indicated that the SC06 supplementation not only improved the ISC regeneration, but also resulted in upregulation of aryl hydrocarbon receptor (AhR) in LPS-challenge piglets. Further studies showed that SC06 also induced ISC differentiation toward goblet cells and inhibited their differentiation to intestinal absorptive cells and enterocytes. The coculture system of SC06 and ileum organoids revealed that SC06 increased the growth of ISCs and repaired LPS-induced organoid damage through activating the AhR/STAT3 signaling pathway. These findings showed that SC06, possibly through the AhR/STAT3 pathway, accelerated ISC proliferation and promoted epithelial barrier healing, providing a potential clinical treatment for IBD. Our research demonstrated that SC06 is effective in preventing intestinal epithelial damage after pathological injury, restoring intestinal homeostasis, and maintaining intestinal epithelial regeneration.
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Affiliation(s)
- Qi Wang
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Fei Wang
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yuanhao Zhou
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xiang Li
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Shujie Xu
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Qian Jin
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Weifen Li
- Key Laboratory of Animal Molecular Nutrition of Education of Ministry, National Engineering Laboratory of Biological Feed Safety and Pollution Prevention and Control, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
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8
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Maryam B, Smith ME, Miller SJ, Natarajan H, Zimmerman KA. Macrophage Ontogeny, Phenotype, and Function in Ischemia Reperfusion-Induced Injury and Repair. KIDNEY360 2024; 5:459-470. [PMID: 38297436 PMCID: PMC11000738 DOI: 10.34067/kid.0000000000000376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 01/22/2024] [Indexed: 02/02/2024]
Abstract
AKI is characterized by a sudden, and usually reversible, decline in kidney function. In mice, ischemia-reperfusion injury (IRI) is commonly used to model the pathophysiologic features of clinical AKI. Macrophages are a unifying feature of IRI as they regulate both the initial injury response as well as the long-term outcome following resolution of injury. Initially, macrophages in the kidney take on a proinflammatory phenotype characterized by the production of inflammatory cytokines, such as CCL2 (monocyte chemoattractant protein 1), IL-6, IL-1 β , and TNF- α . Release of these proinflammatory cytokines leads to tissue damage. After resolution of the initial injury, macrophages take on a reparative role, aiding in tissue repair and restoration of kidney function. By contrast, failure to resolve the initial injury results in prolonged inflammatory macrophage accumulation and increased kidney damage, fibrosis, and the eventual development of CKD. Despite the extensive amount of literature that has ascribed these functions to M1/M2 macrophages, a recent paradigm shift in the macrophage field now defines macrophages on the basis of their ontological origin, namely monocyte-derived and tissue-resident macrophages. In this review, we focus on macrophage phenotype and function during IRI-induced injury, repair, and transition to CKD using both the classic (M1/M2) and novel (ontological origin) definition of kidney macrophages.
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Affiliation(s)
- Bibi Maryam
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Morgan E. Smith
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Sarah J. Miller
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Hariharasudan Natarajan
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Kurt A. Zimmerman
- Division of Nephrology, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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Anders HJ, Andrassy J, Lichtnekert J. Regulators of necroinflammation in acute kidney injury. Kidney Int 2024; 105:22-25. [PMID: 38182296 DOI: 10.1016/j.kint.2023.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 01/07/2024]
Abstract
Interleukin (IL)-22 is unique among the ILs as it elicits direct effects on kidney epithelia and regulates cell survival in a context-dependent manner. Studies published in Kidney International and other journals demonstrate opposing roles of IL-22 (e.g., in models of acute kidney injury). In the early necroinflammation phase of acute kidney injury, IL-22 promotes tubular cell death, whereas it enhances the proliferation and regeneration of epithelial barrier function in the healing phase of injured tubules.
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Affiliation(s)
- Hans-Joachim Anders
- Renal Division, Department of Medicine IV, University Hospital of the Ludwig Maximilian University, Munich, Germany.
| | - Joachim Andrassy
- Division of General, Visceral, Vascular and Transplant Surgery, Hospital of Ludwig Maximilians University, Munich, Germany
| | - Julia Lichtnekert
- Renal Division, Department of Medicine IV, University Hospital of the Ludwig Maximilian University, Munich, Germany
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Wang K, Zhou M, Si H, Ma J. Gut microbiota-mediated IL-22 alleviates metabolic inflammation. Life Sci 2023; 334:122229. [PMID: 37922980 DOI: 10.1016/j.lfs.2023.122229] [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: 08/28/2023] [Revised: 10/25/2023] [Accepted: 10/29/2023] [Indexed: 11/06/2023]
Abstract
Low-grade chronic inflammation, also known as metabolic inflammation, promotes the development of metabolic diseases. Increasing evidence suggests that changes in gut microbes and metabolites disrupt the integrity of the gut barrier and exert significant effects on the metabolism of various tissues, including the liver and adipose tissue, thereby contributing to metabolic inflammation. We observed that IL-22 is a key signaling molecule that serves as a bridge between intestinal microbes and the host, effectively alleviating metabolic inflammation by modulating the host immunomodulatory network. Here, we focused on elucidating the underlying mechanisms by which the gut microbiota and their metabolites reduce inflammation via IL-22, highlighting the favorable impact of IL-22 on metabolic inflammation. Furthermore, we discuss the potential of IL-22 as a therapeutic target for the management of metabolic inflammation and related diseases.
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Affiliation(s)
- Kaijun Wang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, Guangxi, China; Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, Hunan, China
| | - Miao Zhou
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, Hunan, China
| | - Hongbin Si
- College of Animal Science and Technology, Guangxi University, Nanning 530004, Guangxi, China
| | - Jie Ma
- College of Animal Science and Technology, Guangxi University, Nanning 530004, Guangxi, China.
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Li N, Han L, Wang X, Qiao O, Zhang L, Gong Y. Biotherapy of experimental acute kidney injury: emerging novel therapeutic strategies. Transl Res 2023; 261:69-85. [PMID: 37329950 DOI: 10.1016/j.trsl.2023.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
Acute kidney injury (AKI) is a complex and heterogeneous disease with high incidence and mortality, posing a serious threat to human life and health. Usually, in clinical practice, AKI is caused by crush injury, nephrotoxin exposure, ischemia-reperfusion injury, or sepsis. Therefore, most AKI models for pharmacological experimentation are based on this. The current research promises to develop new biological therapies, including antibody therapy, non-antibody protein therapy, cell therapy, and RNA therapy, that could help mitigate the development of AKI. These approaches can promote renal repair and improve systemic hemodynamics after renal injury by reducing oxidative stress, inflammatory response, organelles damage, and cell death, or activating cytoprotective mechanisms. However, no candidate drugs for AKI prevention or treatment have been successfully translated from bench to bedside. This article summarizes the latest progress in AKI biotherapy, focusing on potential clinical targets and novel treatment strategies that merit further investigation in future pre-clinical and clinical studies.
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Affiliation(s)
- Ning Li
- Institute of Disaster and Emergency Medicine, Medical College, Tianjin University, Nankai District, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Lu Han
- Institute of Disaster and Emergency Medicine, Medical College, Tianjin University, Nankai District, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Xinyue Wang
- Institute of Disaster and Emergency Medicine, Medical College, Tianjin University, Nankai District, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Ou Qiao
- Institute of Disaster and Emergency Medicine, Medical College, Tianjin University, Nankai District, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Li Zhang
- Institute of Disaster and Emergency Medicine, Medical College, Tianjin University, Nankai District, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Yanhua Gong
- Institute of Disaster and Emergency Medicine, Medical College, Tianjin University, Nankai District, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
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12
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Mansur F, Arshad T, Liska V, Manzoor S. Interleukin-22 promotes the proliferation and migration of hepatocellular carcinoma cells via the phosphoinositide 3-kinase (PI3K/AKT) signaling pathway. Mol Biol Rep 2023:10.1007/s11033-023-08542-x. [PMID: 37264148 DOI: 10.1007/s11033-023-08542-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/19/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND Interleukin-22 (IL-22) is a pro-inflammatory cytokine released during the immune response in chronic liver injury. Although IL-22 mediates tissue regeneration, its uncontrolled production may generate a carcinogenic environment resulting in hepatocellular carcinoma (HCC). This study aims to identify the effect of IL-22 on anti-apoptotic and metastatic genes and the molecular pathways responsible for IL-22-mediated hepatic carcinogenesis. METHODS AND RESULTS Three cancerous liver lines, HepG2, SNU-387, Huh7, and one normal liver line, THLE2, were treated with IL-22. RT-qPCR analysis was conducted to study the role of IL-22 in altering the expression levels of anti-apoptotic genes, MCL-1 and BCL-2, and metastatic genes, MMP-7 and MMP-9. A significant increase in expression levels of these genes was observed after IL-22 treatment. Furthermore, to explore the major pathways involved in IL-22-mediated upregulation of anti-apoptotic and metastatic genes, cells were treated with inhibitors of JAK/STAT and PI3K/AKT pathways along with IL-22. Resultantly, a significant decrease in expression levels of target genes was observed, indicating the involvement of JAK/STAT and PI3K/AKT signaling cascades in IL-22-mediated oncogenesis. Finally, Cell Scratch assay was performed to check the effect of IL-22 and inhibitors of JAK/STAT and PI3K/AKT on the metastatic potential of liver cells. While migration was observed in Huh7 and THLE2 cells treated with IL-22, no migration was observed in cells treated with IL-22 along with JAK/STAT and PI3K/AKT inhibitors. Results indicate that IL-22 encourages metastasis in HCC cells via the JAK/STAT and PI3K/AKT pathways. CONCLUSION Results showed that IL-22 upregulates anti-apoptotic and metastatic genes in HCC through JAK/STAT and PI3K/AKT signaling pathways.
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Affiliation(s)
- Fizzah Mansur
- Molecular Virology and Immunology Research Group, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Tanzeela Arshad
- Molecular Virology and Immunology Research Group, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Vaclav Liska
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Sobia Manzoor
- Molecular Virology and Immunology Research Group, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia.
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Han Z, Chen L, Peng H, Zheng H, Lin Y, Peng F, Fan Y, Xie X, Yang S, Wang Z, Yuan L, Wei X, Chen H. The role of thyroid hormone in the renal immune microenvironment. Int Immunopharmacol 2023; 119:110172. [PMID: 37086678 DOI: 10.1016/j.intimp.2023.110172] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/29/2023] [Accepted: 04/07/2023] [Indexed: 04/24/2023]
Abstract
Thyroid hormones are essential for proper kidney growth and development. The kidney is not only the organ of thyroid hormone metabolism but also the target organ of thyroid hormone. Kidney disease is a common type of kidney damage, mainly including different types of acute kidney injury, chronic kidney disease, diabetic nephropathy, lupus nephritis, and renal cell carcinoma. The kidney is often damaged by an immune response directed against its antigens or a systemic immune response. A variety of immune cells in the innate and adaptive immune systems, including neutrophils, macrophages, dendritic cells, T lymphocytes, and B lymphocytes, is essential for maintaining immune homeostasis and preventing autoimmune kidney disease. Recent studies have found that thyroid hormone plays an indispensable role in the immune microenvironment of various kidney diseases. Thyroid hormones regulate the activity of neutrophils, and dendritic cells express triiodothyronine receptors. Compared to hypothyroidism, hyperthyroidism has a greater effect on neutrophils. Furthermore, in adaptive immune systems, thyroid hormone may activate T lymphocytes through several underlying mechanisms, such as mediating NF-κB, protein kinase C signalling pathways, and β-adrenergic receptors, leading to increased T lymphocyte activation. The present review discusses the effects of thyroid hormone metabolism regulation in the immune microenvironment on the function of various immune cells, especially neutrophils, macrophages, dendritic cells, T lymphocytes, and B lymphocytes. Although there are not enough data at this stage to conclude the clinical relevance of these findings, thyroid hormone metabolism may influence autoimmune kidney disease by regulating the renal immune microenvironment.
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Affiliation(s)
- Zhongyu Han
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liuyan Chen
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyao Peng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongying Zheng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumeng Lin
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fang Peng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunhe Fan
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiuli Xie
- School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Simin Yang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhanzhan Wang
- Lianyungang Clinical Medical College of Nanjing Medical University, Lianyungang, China
| | - Lan Yuan
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Xiuyan Wei
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Zhao ZB, Marschner JA, Iwakura T, Li C, Motrapu M, Kuang M, Popper B, Linkermann A, Klocke J, Enghard P, Muto Y, Humphreys BD, Harris HE, Romagnani P, Anders HJ. Tubular Epithelial Cell HMGB1 Promotes AKI-CKD Transition by Sensitizing Cycling Tubular Cells to Oxidative Stress: A Rationale for Targeting HMGB1 during AKI Recovery. J Am Soc Nephrol 2023; 34:394-411. [PMID: 36857499 PMCID: PMC10103235 DOI: 10.1681/asn.0000000000000024] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 10/22/2022] [Indexed: 01/22/2023] Open
Abstract
SIGNIFICANCE STATEMENT Cells undergoing necrosis release extracellular high mobility group box (HMGB)-1, which triggers sterile inflammation upon AKI in mice. Neither deletion of HMGB1 from tubular epithelial cells, nor HMGB1 antagonism with small molecules, affects initial ischemic tubular necrosis and immediate GFR loss upon unilateral ischemia/reperfusion injury (IRI). On the contrary, tubular cell-specific HMGB1 deficiency, and even late-onset pharmacological HMGB1 inhibition, increased functional and structural recovery from AKI, indicating that intracellular HMGB1 partially counters the effects of extracellular HMGB1. In vitro studies indicate that intracellular HMGB1 decreases resilience of tubular cells from prolonged ischemic stress, as in unilateral IRI. Intracellular HMGB1 is a potential target to enhance kidney regeneration and to improve long-term prognosis in AKI. BACKGROUND Late diagnosis is a hurdle for treatment of AKI, but targeting AKI-CKD transition may improve outcomes. High mobility group box-1 (HMGB1) is a nuclear regulator of transcription and a driver of necroinflammation in AKI. We hypothesized that HMGB1 would also modulate AKI-CKD transition in other ways. METHODS We conducted single-cell transcriptome analysis of human and mouse AKI and mouse in vivo and in vitro studies with tubular cell-specific depletion of Hmgb1 and HMGB1 antagonists. RESULTS HMGB1 was ubiquitously expressed in kidney cells. Preemptive HMGB1 antagonism with glycyrrhizic acid (Gly) and ethyl pyruvate (EP) did not affect postischemic AKI but attenuated AKI-CKD transition in a model of persistent kidney hypoxia. Consistently, tubular Hmgb1 depletion in Pax8 rtTA, TetO Cre, Hmgb1fl/fl mice did not protect from AKI, but from AKI-CKD transition. In vitro studies confirmed that absence of HMGB1 or HMGB1 inhibition with Gly and EP does not affect ischemic necrosis of growth-arrested differentiated tubular cells but increased the resilience of cycling tubular cells that survived the acute injury to oxidative stress. This effect persisted when neutralizing extracellular HMGB1 with 2G7. Consistently, late-onset HMGB1 blockade with EP started after the peak of ischemic AKI in mice prevented AKI-CKD transition, even when 2G7 blocked extracellular HMGB1. CONCLUSION Treatment of AKI could become feasible when ( 1 ) focusing on long-term outcomes of AKI; ( 2 ) targeting AKI-CKD transition with drugs initiated after the AKI peak; and ( 3 ) targeting with drugs that block HMGB1 in intracellular and extracellular compartments.
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Affiliation(s)
- Zhi Bo Zhao
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Julian A. Marschner
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Takamasa Iwakura
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Chenyu Li
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Manga Motrapu
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Meisi Kuang
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Bastian Popper
- Biomedical Center, Core Facility Animal Models, LMU München, Munich, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Jan Klocke
- Department of Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Philipp Enghard
- Department of Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Yoshiharu Muto
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Benjamin D. Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Department of Developmental Biology, Washington University in St. Louis, St. Louis, Missouri
| | - Helena Erlandsson Harris
- Departments of Rheumatology and of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Paola Romagnani
- Department of Experimental and Biomedical Sciences "Mario Serio" and Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy
| | - Hans-Joachim Anders
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
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15
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Cao Z, Zhao H, Fan J, Shen Y, Han L, Jing G, Zeng X, Jin X, Zhu Z, Bian Q, Nan Y, Hu X, Mei X, Ju D, Yang P. Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response. Cell Death Dis 2023; 9:8. [PMID: 36646672 PMCID: PMC9842640 DOI: 10.1038/s41420-023-01304-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/26/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023]
Abstract
The pathogenesis of diabetic kidney disease (DKD) is complicated. Current clinical treatments fail to achieve satisfactory efficacy in the prevention of DKD progression, it urgently needs novel and effective treatment for DKD. In this study, we firstly demonstrated that renal lipid metabolism abnormality and inflammation significantly changed in DKD conditions by mining public transcriptomic data of DKD patient samples. KEGG analysis further exhibited the critical role of vascular endothelial growth factor B (VEGF-B) and interleukin 17A (IL-17A) signal pathways in DKD progression, indicating that VEGF-B and IL-17A might be the promising targets for DKD treatment. Then the potential of a novel combination therapy, anti-VEGF-B plus anti-IL-17A antibody, was evaluated for DKD treatment. Our results demonstrated that simultaneous blockade of VEGF-B and IL-17A signaling with their neutralizing antibodies alleviated renal damage and ameliorated renal function. The therapeutic effectiveness was not only related to the reduced lipid deposition especially the neutral lipids in kidney but also associated with the decreased inflammation response. Moreover, the therapy alleviated renal fibrosis by reducing collagen deposition and the expression of fibronectin and α-SMA in kidney tissues. RNA-seq analysis indicated that differential expression genes (DEGs) in db/db mice were significantly clustered into lipid metabolism, inflammation, fibrosis and DKD pathology-related pathways, and 181 of those DEGs were significantly reversed by the combinatory treatment, suggesting the underlying mechanism of administration of anti-VEGF-B and anti-IL-17A antibodies in DKD treatment. Taken together, this study identified that renal lipid metabolism abnormality and inflammation were critically involved in the progression of DKD, and simultaneous blockade of VEGF-B and IL-17A signaling represents a potential DKD therapeutic strategy.
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Affiliation(s)
- Zhonglian Cao
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China ,grid.8547.e0000 0001 0125 2443Instrumental Analysis Center, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Hui Zhao
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Jiajun Fan
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Yilan Shen
- grid.73113.370000 0004 0369 1660Department of Nephrology, Changhai Hospital, Second Military Medical University, 200433 Shanghai, China
| | - Lei Han
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Guangjun Jing
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Xian Zeng
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Xin Jin
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Zeguo Zhu
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Qi Bian
- grid.73113.370000 0004 0369 1660Department of Nephrology, Changhai Hospital, Second Military Medical University, 200433 Shanghai, China
| | - Yanyang Nan
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Xiaozhi Hu
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Xiaobin Mei
- grid.73113.370000 0004 0369 1660Department of Nephrology, Changhai Hospital, Second Military Medical University, 200433 Shanghai, China ,Department of Nephrology, Gongli Hospital of Shanghai Pudong New Area, 200135 Shanghai, China
| | - Dianwen Ju
- grid.8547.e0000 0001 0125 2443Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, 201203 Shanghai, China
| | - Ping Yang
- grid.8547.e0000 0001 0125 2443Instrumental Analysis Center, Fudan University School of Pharmacy, 201203 Shanghai, China
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16
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Vallés PG, Gil Lorenzo AF, Garcia RD, Cacciamani V, Benardon ME, Costantino VV. Toll-like Receptor 4 in Acute Kidney Injury. Int J Mol Sci 2023; 24:ijms24021415. [PMID: 36674930 PMCID: PMC9864062 DOI: 10.3390/ijms24021415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 01/13/2023] Open
Abstract
Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be connected with intrarenal and systemic inflammation. The innate immune system plays an important role as the first defense response mechanism to tissue injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response, plays a pivotal role in the pathogenesis of acute kidney injury. Pathogen-associated molecular patterns (PAMPS), which are the conserved microbial motifs, are sensed by these receptors. Endogenous molecules generated during tissue injury, and labeled as damage-associated molecular pattern molecules (DAMPs), also activate pattern recognition receptors, thereby offering an understanding of sterile types of inflammation. Excessive, uncontrolled and/or sustained activation of TLR4, may lead to a chronic inflammatory state. In this review we describe the role of TLR4, its endogenous ligands and activation in the inflammatory response to ischemic/reperfusion-induced AKI and sepsis-associated AKI. The potential regeneration signaling patterns of TLR4 in acute kidney injury, are also discussed.
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Affiliation(s)
- Patricia G. Vallés
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
- IMBECU-CONICET (Instituto de Medicina y Biología Experimental de Cuyo—Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza 5500, Argentina
- Correspondence:
| | - Andrea Fernanda Gil Lorenzo
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
| | - Rodrigo D. Garcia
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
| | - Valeria Cacciamani
- IMBECU-CONICET (Instituto de Medicina y Biología Experimental de Cuyo—Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza 5500, Argentina
| | - María Eugenia Benardon
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
| | - Valeria Victoria Costantino
- IMBECU-CONICET (Instituto de Medicina y Biología Experimental de Cuyo—Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza 5500, Argentina
- Área de Biología Celular, Departamento de Morfofisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
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17
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Li J, Gong X. Bibliometric and visualization analysis of kidney repair associated with acute kidney injury from 2002 to 2022. Front Pharmacol 2023; 14:1101036. [PMID: 37153766 PMCID: PMC10157647 DOI: 10.3389/fphar.2023.1101036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/12/2023] [Indexed: 05/10/2023] Open
Abstract
Background: Renal repair is closely related to the prognosis of acute kidney injury (AKI) and has attracted increasing attention in the research field. However, there is a lack of a comprehensive bibliometric analysis in this research area. This study aims at exploring the current status and hotspots of renal repair research in AKI from the perspective of bibliometrics. Methods: Studies published between 2002 and 2022 related to kidney repair after AKI were collected from Web of Science core collection (WoSCC) database. Bibliometric measurement and knowledge graph analysis to predict the latest research trends in the field were performed using bibliometrics software CiteSpace and VOSviewer. Results: The number of documents related to kidney repair after AKI has steadily increased over 20 years. The United States and China contribute more than 60% of documents and are the main drivers of research in this field. Harvard University is the most active academic institution that contributes the most documents. Humphreys BD and Bonventre JV are the most prolific authors and co-cited authors in the field. The American Journal of Physiology-Renal Physiology and Journal of the American Society of Nephrology are the most popular journals in the field with the greatest number of documents. "exosome", "macrophage polarization", "fibroblast", and" aki-ckd transition" are high-frequency keywords in this field in recent years. Extracellular vesicles (including exosomes), macrophage polarization, cell cycle arrest, hippo pathway, and sox9 are current research hotspots and potential targets in this field. Conclusion: This is the first comprehensive bibliometric study on the knowledge structure and development trend of AKI-related renal repair research in recent years. The results of the study comprehensively summarize and identify research frontiers in AKI-related renal repair.
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18
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Schütte-Nütgen K, Edeling M, Kentrup D, Heitplatz B, Van Marck V, Zarbock A, Meersch-Dini M, Pavenstädt H, Reuter S. Interleukin 24 promotes cell death in renal epithelial cells and is associated with acute renal injury. Am J Transplant 2022; 22:2548-2559. [PMID: 35801504 DOI: 10.1111/ajt.17143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 06/02/2022] [Accepted: 07/03/2022] [Indexed: 01/25/2023]
Abstract
Ischemia-reperfusion injury is a major cause of acute kidney injury. Many cytokines are involved in the pathogenesis of renal ischemia-reperfusion injury. IL24 is a member of the IL10 family and has gained importance because of its apoptosis-inducing effects in tumor disease besides its immunoregulative function. Littles is known about the role of IL24 in kidney disease. Using a mouse model, we found that IL24 is upregulated in the kidney after renal ischemia-reperfusion injury and that tubular epithelial cells and infiltrating inflammatory cells are the source of IL24. Mice lacking IL24 are protected from renal injury and inflammation. Cell culture studies showed that IL24 induces apoptosis in renal tubular epithelial cells, which is accompanied by an increased endoplasmatic reticulum stress response. Moreover, IL24 induces robust expression of endogenous IL24 in tubular cells, fostering ER-stress and apoptosis. In kidney transplant recipients with delayed graft function and patients at high risk to develop acute kidney injury after cardiac surgery IL24 is upregulated in the kidney and serum. Taken together, IL24 can serve as a biomarker, plays an important mechanistic role involving both extracellular and intracellular targets, and is a promising therapeutic target in patients at risk of or with ischemia-induced acute kidney injury.
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Affiliation(s)
- Katharina Schütte-Nütgen
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
| | - Maria Edeling
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
| | - Dominik Kentrup
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany.,Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, Illinois, USA
| | - Barbara Heitplatz
- Department of Pathology, University Hospital Münster, Münster, Germany
| | - Veerle Van Marck
- Department of Pathology, University Hospital Münster, Münster, Germany
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Melanie Meersch-Dini
- Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Hermann Pavenstädt
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
| | - Stefan Reuter
- Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
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19
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Wang Z, Zhang C. From AKI to CKD: Maladaptive Repair and the Underlying Mechanisms. Int J Mol Sci 2022; 23:ijms231810880. [PMID: 36142787 PMCID: PMC9504835 DOI: 10.3390/ijms231810880] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 12/03/2022] Open
Abstract
Acute kidney injury (AKI) is defined as a pathological condition in which the glomerular filtration rate decreases rapidly over a short period of time, resulting in changes in the physiological function and tissue structure of the kidney. An increasing amount of evidence indicates that there is an inseparable relationship between acute kidney injury and chronic kidney disease (CKD). With the progress in research in this area, researchers have found that the recovery of AKI may also result in the occurrence of CKD due to its own maladaptation and other potential mechanisms, which involve endothelial cell injury, inflammatory reactions, progression to fibrosis and other pathways that promote the progress of the disease. Based on these findings, this review summarizes the occurrence and potential mechanisms of maladaptive repair in the progression of AKI to CKD and explores possible treatment strategies in this process so as to provide a reference for the inhibition of the progression of AKI to CKD.
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20
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Fu Y, Xiang Y, Li H, Chen A, Dong Z. Inflammation in kidney repair: Mechanism and therapeutic potential. Pharmacol Ther 2022; 237:108240. [PMID: 35803367 DOI: 10.1016/j.pharmthera.2022.108240] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 02/07/2023]
Abstract
The kidney has a remarkable ability of repair after acute kidney injury (AKI). However, when injury is severe or persistent, the repair is incomplete or maladaptive and may lead to chronic kidney disease (CKD). Maladaptive kidney repair involves multiple cell types and multifactorial processes, of which inflammation is a key component. In the process of inflammation, there is a bidirectional interplay between kidney parenchymal cells and the immune system. The extensive and complex crosstalk between renal tubular epithelial cells and interstitial cells, including immune cells, fibroblasts, and endothelial cells, governs the repair and recovery of the injured kidney. Further research in this field is imperative for the discovery of biomarkers and promising therapeutic targets for kidney repair. In this review, we summarize the latest progress in the immune response and inflammation during maladaptive kidney repair, analyzing the interaction between immune cells and intrinsic kidney cells, pointing out the potentialities of inflammation-related pathways as therapeutic targets, and discussing the challenges and future research prospects in this field.
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Affiliation(s)
- Ying Fu
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Yu Xiang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Honglin Li
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Anqun Chen
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China
| | - Zheng Dong
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha 410011, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
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21
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Lu X, Crowley SD. Actions of Dendritic Cells in the Kidney during Hypertension. Compr Physiol 2022; 12:4087-4101. [PMID: 35950656 DOI: 10.1002/cphy.c210050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The immune response plays a critical role in the pathogenesis of hypertension, and immune cell populations can promote blood pressure elevation via actions in the kidney. Among these cell lineages, dendritic cells (DCs), the most potent antigen-presenting cells, play a central role in regulating immune response during hypertension and kidney disease. DCs have different subtypes, and renal DCs are comprised of the CD103+ CD11b- and CD103- CD11b+ subsets. DCs become mature and express costimulatory molecules on their surface once they encounter antigen. Isolevuglandin-modified proteins function as antigens to activate DCs and trigger them to stimulate T cells. Activated T cells accumulate in the hypertensive kidney, release effector cytokines, promote renal oxidative stress, and promote renal salt and water retention. Individual subsets of activated T cells can secrete tumor necrosis factor-alpha, interleukin-17A, and interferon-gamma, each of which has augmented the elevation of blood pressure in hypertensive models by enhancing renal sodium transport. Fms-like tyrosine kinase 3 ligand-dependent classical DCs are required to sustain the full hypertensive response, but C-X3 -C chemokine receptor 1 positive DCs do not regulate blood pressure. Excess sodium enters the DC through transporters to activate DCs, whereas the ubiquitin editor A20 in dendritic cells constrains blood pressure elevation by limiting T cell activation. By contrast, activation of the salt sensing kinase, serum/glucocorticoid kinase 1 in DCs exacerbates salt-sensitive hypertension. This article discusses recent studies illustrating mechanisms through which DC-T cell interactions modulate levels of pro-hypertensive mediators to regulate blood pressure via actions in the kidney. © 2022 American Physiological Society. Compr Physiol 12:1-15, 2022.
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Affiliation(s)
- Xiaohan Lu
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA
| | - Steven D Crowley
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA
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22
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Wang W, Lu Y, Hu X, Li H, Li X, Xiao C, Meng T, Peng L, Gan L, Zhou Q, Xiao P, Tang R. Interleukin-22 exacerbates angiotensin II-induced hypertensive renal injury. Int Immunopharmacol 2022; 109:108840. [PMID: 35567856 DOI: 10.1016/j.intimp.2022.108840] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/25/2022] [Accepted: 05/03/2022] [Indexed: 11/05/2022]
Abstract
Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4+ T cells and the secreted inflammatory cytokines contribute to the progress of HRI. However, the exact mechanisms remain unidentified in HRI, and there is still a shortage of effective treatments. Here, we aim to explore the role of interleukin-22 (IL-22) and its underlying mechanism in HRI. Serum IL-22 level and peripheral Th22 cells frequency in patients with HRI were detected by ELISA and flow cytometry respectively. Angiotension II (Ang II) was infused subcutaneously to C57BL/6 mice for 28 days. Hypertensive mice were treated with recombinant IL-22 (rIL-22), anti-IL-22 antibody, or JAK2/STAT3 pathway blocker AG-490 respectively. Blood pressure (BP), urinary albumin/creatinine ratio (UACR), serum creatinine (Scr) and renal histopathology were measured; renal Th22 cells proportion were evaluated; inflammatory factors were evaluated by ELISA; JAK2/STAT3 pathway and fibrosis related factors expression in kidney were detected by Western blot. Serum IL-22 and Th22 cells proportion in kidney of mice were elevated after Ang II infusion. Compared to Ang II-infused mice, treatment with rIL-22 resulted in further increased UACR, Scr, renal pathological damage, inflammation and renal fibrosis, accompanied by elevated BP and JAK2/STAT3 pathway activation. Conversely, anti-IL-22 antibody reduced inflammation, renal fibrosis and BP in Ang II treated mice. AG490 could compromised the above effects of rIL-22. Taken together, recombinant IL-22 may aggravate hypertensive renal damage mediated by Ang II in mice, which may be through promoting JAK2/STAT3 pathway activation. Anti-IL-22 antibody exerts the opposite effects. These data suggest the IL-22 signaling maybe a novel therapeutic target for the treatment of hypertensive renal injury.
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Affiliation(s)
- Wei Wang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang Lu
- Department of Nephrology, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Xueling Hu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Huihui Li
- Department of Nephrology, Chongqing City Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xiaozhao Li
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chenggen Xiao
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ting Meng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Peng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lu Gan
- Department of Nephrology, First People's Hospital of Yunnan, Kunming, Yunnan, China
| | - Qiaoling Zhou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ping Xiao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Chen H, Liu N, Zhuang S. Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy. Front Immunol 2022; 13:934299. [PMID: 35911736 PMCID: PMC9326079 DOI: 10.3389/fimmu.2022.934299] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Acute kidney injury (AKI) is a renal disease with a high incidence and mortality. Currently, there are no targeted therapeutics for preventing and treating AKI. Macrophages, important players in mammalian immune response, are involved in the multiple pathological processes of AKI. They are dynamically activated and exhibit a diverse spectrum of functional phenotypes in the kidney after AKI. Targeting the mechanisms of macrophage activation significantly improves the outcomes of AKI in preclinical studies. In this review, we summarize the role of macrophages and the underlying mechanisms of macrophage activation during kidney injury, repair, regeneration, and fibrosis and provide strategies for macrophage-targeted therapies.
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Affiliation(s)
- Hui Chen
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, United States
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24
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Mechanisms for Bile Acids CDCA- and DCA-Stimulated Hepatic Spexin Expression. Cells 2022; 11:cells11142159. [PMID: 35883602 PMCID: PMC9316865 DOI: 10.3390/cells11142159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/03/2022] [Accepted: 07/05/2022] [Indexed: 11/20/2022] Open
Abstract
Spexin (SPX) is a novel peptide involved in glucose and lipid metabolism and suppresses hepatic total bile acid levels by inhibiting hepatic cholesterol 7α-hydroxylase 1 expression. As important mediators for glycolysis/gluconeogenesis and lipid metabolism, the effects of bile acids on SPX expression is yet to be understood. By using SMMC7721 and BEL-7402 cell lines, we screened the effects of bile acids and found that chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) can stimulate SPX gene transcription. Both CDCA and DCA were able to stimulate SPX mRNA expression in the liver but not colon and ileum in mice. In SMMC7721 and BEL-7402 cells, CDCA- and DCA-induced SPX promoter activity was mimicked by bile acid receptor FXR and TGR5 activation and suppressed by FXR and TGR5 silencing. Adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP) activators significantly increased SPX promoter activity whereas the inhibitors for AC/CAMP/protein kinase A (PKA) and mitogen-activated protein kinases (MAPK) pathway attenuated CDCA- and DCA-induced SPX transcription. Thus, CDCA and DCA stimulate SPX expression at the hepatic level through FXR and TGR5 mediated AC/cAMP/PKA and MAPK cascades.
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25
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Immunometabolic rewiring of tubular epithelial cells in kidney disease. Nat Rev Nephrol 2022; 18:588-603. [PMID: 35798902 DOI: 10.1038/s41581-022-00592-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2022] [Indexed: 12/20/2022]
Abstract
Kidney tubular epithelial cells (TECs) have a crucial role in the damage and repair response to acute and chronic injury. To adequately respond to constant changes in the environment, TECs have considerable bioenergetic needs, which are supported by metabolic pathways. Although little is known about TEC metabolism, a number of ground-breaking studies have shown that defective glucose metabolism or fatty acid oxidation in the kidney has a key role in the response to kidney injury. Imbalanced use of these metabolic pathways can predispose TECs to apoptosis and dedifferentiation, and contribute to lipotoxicity and kidney injury. The accumulation of lipids and aberrant metabolic adaptations of TECs during kidney disease can also be driven by receptors of the innate immune system. Similar to their actions in innate immune cells, pattern recognition receptors regulate the metabolic rewiring of TECs, causing cellular dysfunction and lipid accumulation. TECs should therefore be considered a specialized cell type - like cells of the innate immune system - that is subject to regulation by immunometabolism. Targeting energy metabolism in TECs could represent a strategy for metabolically reprogramming the kidney and promoting kidney repair.
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26
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Shelke V, Kale A, Anders HJ, Gaikwad AB. Epigenetic regulation of Toll-like receptors 2 and 4 in kidney disease. J Mol Med (Berl) 2022; 100:1017-1026. [PMID: 35704060 DOI: 10.1007/s00109-022-02218-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/25/2022]
Abstract
Kidney disease affects more than 10% of the worldwide population and causes significant morbidity and mortality. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) play a pivotal role in the progression of kidney disease. These epigenetic mechanisms are reversible and majorly involved in regulating gene expression of inflammatory, fibrotic, and apoptotic proteins. Emerging data suggest that the Toll-like receptor 2 and Toll-like receptor 4 (TLR2 and TLR4) are expressed by almost all types of kidney cells and known for promoting inflammation by recognizing damage-associated molecular proteins (DAMPs). Epigenetic mechanisms regulate TLR2 and TLR4 signaling in various forms of kidney disease where different histone modifications promote the transcription of the TLR2 and TLR4 gene and its ligand high mobility group box protein 1 (HMGB1). Moreover, numerous long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) modulate TLR2 and TLR4 signaling in kidney disease. However, the precise mechanisms behind this regulation are still enigmatic. Studying the epigenetic mechanisms involved in the regulation of TLR2 and TLR4 signaling in the development of kidney disease may help in understanding and finding novel therapeutic strategies. This review discusses the intricate relationship of epigenetic mechanisms with TLR2 and TLR4 in different forms of kidney diseases. In addition, we discuss the different lncRNAs and miRNAs that regulate TLR2 and TLR4 as potential therapeutic targets in kidney disease.
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Affiliation(s)
- Vishwadeep Shelke
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, 333 031, Rajasthan, India
| | - Ajinath Kale
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, 333 031, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, 80336, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, 333 031, Rajasthan, India.
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27
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Chen T, Fang Z, Zhu J, Lv Y, Li D, Pan J. ACE2 Promoted by STAT3 Activation Has a Protective Role in Early-Stage Acute Kidney Injury of Murine Sepsis. Front Med (Lausanne) 2022; 9:890782. [PMID: 35733865 PMCID: PMC9207930 DOI: 10.3389/fmed.2022.890782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 04/25/2022] [Indexed: 12/04/2022] Open
Abstract
Sepsis-induced AKI (SIAKI) is the most common complication with unacceptable mortality in hospitalized and critically ill patients. The pathophysiology of the development of SIAKI is still poorly understood. Our recent work has demonstrated the role of signal transducer and activator of transcription 3 (STAT3) pathways in regulating inflammation and coagulation in sepsis. We hypothesized that STAT3 activation has a critical role in early-stage SIAKI. The early-stage SIAKI model was established in cecal ligation and puncture (CLP) mice, which recapitulates the clinical and renal pathological features of early-stage AKI patients. Brush border loss (BBL) was the specific pathological feature of acute tubular injury in early-stage AKI. The role of STAT3 signaling and angiotension system in early-stage SIAKI was evaluated. The STAT3 activation (increased pSTAT3) and increased angiotensin-converting enzyme 2 (ACE2) expressions were observed in CLP mice. The low responsive expressions of pSTAT3 and ACE2 to septic inflammation in CLP AKI mice were associated with BBL. Correlation analysis of proteins' expressions showed pSTAT3 expression was significantly positively related to ACE2 expression in CLP mice. Reduced pSTAT3 after S3I201 intervention, which blocked STAT3 phosphorylation, decreased ACE2 expression, and exacerbated tubular injury in early-stage SIAKI. Our data indicate that endogenous increase of ACE2 expression upregulated by STAT3 activation in early-stage SIAKI play protective role against acute tubular injury.
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Affiliation(s)
- Tianxin Chen
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhendong Fang
- Department of Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jianfen Zhu
- Department of Endoscopy Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yinqiu Lv
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Duo Li
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jingye Pan
- Department of Key Laboratory of Intelligent Critical Care and Life Support Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of ICU, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Jingye Pan
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28
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Bando T, Okumura M, Bando Y, Hagiwara M, Hamada Y, Ishimaru Y, Mito T, Kawaguchi E, Inoue T, Agata K, Noji S, Ohuchi H. Toll signalling promotes blastema cell proliferation during cricket leg regeneration via insect macrophages. Development 2022; 149:272415. [PMID: 34622924 DOI: 10.1242/dev.199916] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022]
Abstract
Hemimetabolous insects, such as the two-spotted cricket Gryllus bimaculatus, can recover lost tissues, in contrast to the limited regenerative abilities of human tissues. Following cricket leg amputation, the wound surface is covered by the wound epidermis, and plasmatocytes, which are insect macrophages, accumulate in the wound region. Here, we studied the function of Toll-related molecules identified by comparative RNA sequencing during leg regeneration. Of the 11 Toll genes in the Gryllus genome, expression of Toll2-1, Toll2-2 and Toll2-5 was upregulated during regeneration. RNA interference (RNAi) of Toll, Toll2-1, Toll2-2, Toll2-3 or Toll2-4 produced regeneration defects in more than 50% of crickets. RNAi of Toll2-2 led to a decrease in the ratio of S- and M-phase cells, reduced expression of JAK/STAT signalling genes, and reduced accumulation of plasmatocytes in the blastema. Depletion of plasmatocytes in crickets using clodronate also produced regeneration defects, as well as fewer proliferating cells in the regenerating legs. Plasmatocyte depletion also downregulated the expression of Toll and JAK/STAT signalling genes in the regenerating legs. These results suggest that Spz-Toll-related signalling in plasmatocytes promotes leg regeneration through blastema cell proliferation by regulating the Upd-JAK/STAT signalling pathway.
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Affiliation(s)
- Tetsuya Bando
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama city, Okayama 700-8558, Japan
| | - Misa Okumura
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama city, Okayama 700-8558, Japan
| | - Yuki Bando
- Faculty of Medicine, Okayama University Medical School, 2-5-1, Shikata-cho, Kita-ku, Okayama city, Okayama 700-8558, Japan
| | - Marou Hagiwara
- Faculty of Medicine, Okayama University Medical School, 2-5-1, Shikata-cho, Kita-ku, Okayama city, Okayama 700-8558, Japan
| | - Yoshimasa Hamada
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama city, Okayama 700-8558, Japan
| | - Yoshiyasu Ishimaru
- Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima-cho, Tokushima City, Tokushima 770-8513, Japan
| | - Taro Mito
- Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima-cho, Tokushima City, Tokushima 770-8513, Japan
| | - Eri Kawaguchi
- Division of Biological Science, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake, Sakyo, Kyoto 606-8502, Japan
| | - Takeshi Inoue
- Division of Biological Science, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake, Sakyo, Kyoto 606-8502, Japan
| | - Kiyokazu Agata
- Division of Biological Science, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake, Sakyo, Kyoto 606-8502, Japan
| | - Sumihare Noji
- Division of Bioscience and Bioindustry, Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima-cho, Tokushima City, Tokushima 770-8513, Japan
| | - Hideyo Ohuchi
- Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama city, Okayama 700-8558, Japan
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29
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Ma Q, Luan J, Bai Y, Xu C, Liu F, Chen B, Ju D, Xu H. Interleukin-22 in Renal Protection and Its Pathological Role in Kidney Diseases. Front Immunol 2022; 13:851818. [PMID: 35432360 PMCID: PMC9008451 DOI: 10.3389/fimmu.2022.851818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic kidney injury has gradually become a worldwide public health problem currently affecting approximately 10% of the population and can eventually progress to chronic end-stage renal disease characteristic by the result of epithelial atrophy. Interleukin-22 (IL-22) is a cytokine produced by activated immune cells, while acting mainly on epithelial cells ranging from innate immune response to tissue regeneration to maintain barrier integrity and promote wound healing. Accumulating data suggests that IL-22 has emerged as a fundamental mediator of epithelial homeostasis in the kidney through promoting tissue repair and regeneration, inhibiting oxidative stress, and producing antimicrobial peptides. Binding of IL-22 to its transmembrane receptor complex triggers janus kinase/tyrosine kinase 2 phosphorylation, which further activates a number of downstream cascades, including signal transducer and activator of transcription 3, MAP kinase, and protein kinase B, and initiates a wide array of downstream effects. However, the activation of the IL-22 signaling pathways promotes the activation of complement systems and enhances the infiltration of chemokines, which does harm to the kidney and may finally result in chronic renal failure of different autoimmune kidney diseases, including lupus nephritis, and IgA nephropathy. This review describes current knowledge of the basic features of IL-22, including structure, cellular origin and associated signaling pathways. Also, we summarize the latest progress in understanding the physiological and pathological effects of IL-22 in the kidney, suggesting the potential strategies for the specific application of this cytokine in the treatment of kidney disease.
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Affiliation(s)
- Qianqian Ma
- Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Jingyun Luan
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Yu Bai
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Caili Xu
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Fangyu Liu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bufeng Chen
- Department of Urology, Binzhou Medical University, Binzhou, China
| | - Dianwen Ju
- Department of Biological Medicines, School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Hong Xu
- Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
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30
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Abstract
Macrophages have emerged at the forefront of research in immunology and transplantation because of recent advances in basic science. New findings have illuminated macrophage populations not identified previously, expanded upon traditional macrophage phenotypes, and overhauled macrophage ontogeny. These advances have major implications for the field of transplant immunology. Macrophages are known to prime adaptive immune responses, perpetuate T-cell-mediated rejection and antibody-mediated rejection, and promote allograft fibrosis. In this review, macrophage phenotypes and their role in allograft injury of solid organ transplants will be discussed with an emphasis on kidney transplantation. Additionally, consideration will be given to the prospect of manipulating macrophage phenotypes as cell-based therapy. Innate immunity and macrophages represent important players in allograft injury and a promising target to improve transplant outcomes.
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Affiliation(s)
- Sarah E. Panzer
- Department of Medicine, Division of Nephrology, University of Wisconsin, Madison, WI, United States
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31
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Manrique-Caballero CL, Kellum JA, Gómez H, De Franco F, Giacchè N, Pellicciari R. Innovations and Emerging Therapies to Combat Renal Cell Damage: NAD + As a Drug Target. Antioxid Redox Signal 2021; 35:1449-1466. [PMID: 33499758 PMCID: PMC8905249 DOI: 10.1089/ars.2020.8066] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 01/21/2021] [Accepted: 01/21/2021] [Indexed: 12/29/2022]
Abstract
Significance: Acute kidney injury (AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is defined by an abrupt deterioration in renal function, clinically manifested by increased serum creatinine levels, decreased urine output, or both. To execute all its functions, namely excretion of waste products, fluid/electrolyte balance, and hormone synthesis, the kidney requires incredible amounts of energy in the form of adenosine triphosphate. Recent Advances: Adequate mitochondrial functioning and nicotinamide adenine dinucleotide (NAD+) homeostasis are essential to meet these high energetic demands. NAD+ is a ubiquitous essential coenzyme to many cellular functions. NAD+ as an electron acceptor mediates metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis, serves as a cosubstrate of aging molecules (i.e., sirtuins), participates in DNA repair mechanisms, and mediates mitochondrial biogenesis. Critical Issues: In many forms of AKI and chronic kidney disease, renal function deterioration has been associated with mitochondrial dysfunction and NAD+ depletion. Based on this, therapies aiming to restore mitochondrial function and increase NAD+ availability have gained special attention in the last two decades. Future Directions: Experimental and clinical studies have shown that by restoring mitochondrial homeostasis and increasing renal tubulo-epithelial cells, NAD+ availability, AKI incidence, and chronic long-term complications are significantly decreased. This review covers some general epidemiological and pathophysiological concepts; describes the role of mitochondrial homeostasis and NAD+ metabolism; and analyzes the underlying rationale and role of NAD+ aiming therapies as promising preventive and therapeutic strategies for AKI. Antioxid. Redox Signal. 35, 1449-1466.
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Affiliation(s)
- Carlos L. Manrique-Caballero
- Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - John A. Kellum
- Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Hernando Gómez
- Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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32
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Xu L. The Role of Myeloid Cells in Acute Kidney Injury and Kidney Repair. KIDNEY360 2021; 2:1852-1864. [PMID: 35372990 PMCID: PMC8785849 DOI: 10.34067/kid.0000672021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 09/17/2021] [Indexed: 02/04/2023]
Abstract
AKI remains highly prevalent, yet no optimal therapy is available to prevent it or promote recovery after initial insult. Experimental studies have demonstrated that both innate and adaptive immune responses play a central role during AKI. In response to injury, myeloid cells are first recruited and activated on the basis of specific signals from the damaged microenvironment. The subsequent recruitment and activation state of the immune cells depends on the stage of injury and recovery, reflecting a dynamic and diverse spectrum of immunophenotypes. In this review, we highlight our current understanding of the mechanisms by which myeloid cells contribute to injury, repair, and fibrosis after AKI.
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Affiliation(s)
- Leyuan Xu
- Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
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33
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Jin Y, Zhang M, Li M, Zhang H, Zhao L, Qian C, Li S, Zhang H, Gao M, Pan B, Li R, Wan X, Cao C. SIX1 Activation Is Involved in Cell Proliferation, Migration, and Anti-inflammation of Acute Ischemia/Reperfusion Injury in Mice. Front Mol Biosci 2021; 8:725319. [PMID: 34513929 PMCID: PMC8427868 DOI: 10.3389/fmolb.2021.725319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/11/2021] [Indexed: 11/13/2022] Open
Abstract
Nephrogenic proteins are re-expressed after ischemia/reperfusion (I/R) injury; however, the role of these proteins is still unknown. We found that sine oculis homeobox 1 (SIX1), a developmentally regulated homeoprotein, is reactivated in tubular epithelial cells after I/R injury associated with cell proliferation/migration and anti-inflammation. We demonstrated that SIX1 promoted cell proliferation by upregulating cyclin and glycolytic genes, and might increase cell migration by upregulating the expression of matrix metalloproteinase 9 (MMP9) directly or indirectly in the cell model. Notably, SIX1 targeted the promoters of the amino-terminal enhancer of split (AES) and fused in sarcoma (FUS), which are cofactors of nuclear factor-κB (NF-κB) subunit RELA, and then inhibited the transactivation function of RELA. The expression of monocyte chemotactic protein-1 (MCP-1) was decreased by the SIX1-mediated NF-κB pathway. Our results showed that the expression of cyclin, glycolytic genes, and MMP9 were significantly increased, and the infiltration of monocytes/macrophages (Mophs) was suppressed in SIX1 overexpression kidney at 1, 2, and 3 days after reperfusion. The overexpression of SIX1 resulted in reducing kidney damage from I/R injury in mice by promoting cell proliferation and migration and by inhibiting inflammation. Our study provides evidence that SIX1 involved in cell proliferation, migration, and anti-inflammation in the I/R model, which might be a potential therapeutic target that could be used to ameliorate kidney damage.
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Affiliation(s)
- Yong Jin
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Manling Zhang
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Meishuang Li
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Hong Zhang
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Lihua Zhao
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Cheng Qian
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Shensen Li
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Hao Zhang
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Min Gao
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Binbin Pan
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rongfeng Li
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Xin Wan
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Changchun Cao
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
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Li N, Steiger S, Fei L, Li C, Shi C, Salei N, Schraml BU, Zheng Z, Anders HJ, Lichtnekert J. IRF8-Dependent Type I Conventional Dendritic Cells (cDC1s) Control Post-Ischemic Inflammation and Mildly Protect Against Post-Ischemic Acute Kidney Injury and Disease. Front Immunol 2021; 12:685559. [PMID: 34234783 PMCID: PMC8255684 DOI: 10.3389/fimmu.2021.685559] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/26/2021] [Indexed: 11/13/2022] Open
Abstract
Post-ischemic acute kidney injury and disease (AKI/AKD) involve acute tubular necrosis and irreversible nephron loss. Mononuclear phagocytes including conventional dendritic cells (cDCs) are present during different phases of injury and repair, but the functional contribution of this subset remains controversial. Transcription factor interferon regulatory factor 8 (IRF8) is required for the development of type I conventional dendritic cells (cDC1s) lineage and helps to define distinct cDC1 subsets. We identified one distinct subset among mononuclear phagocyte subsets according to the expression patterns of CD11b and CD11c in healthy kidney and lymphoid organs, of which IRF8 was significantly expressed in the CD11blowCD11chigh subset that mainly comprised cDC1s. Next, we applied a Irf8-deficient mouse line (Irf8fl/flClec9acre mice) to specifically target Clec9a-expressing cDC1s in vivo. During post-ischemic AKI/AKD, these mice lacked cDC1s in the kidney without affecting cDC2s. The absence of cDC1s mildly aggravated the loss of living primary tubule and decline of kidney function, which was associated with decreased anti-inflammatory Tregs-related immune responses, but increased T helper type 1 (TH1)-related and pro-inflammatory cytokines, infiltrating neutrophils and acute tubular cell death, while we also observed a reduced number of cytotoxic CD8+ T cells in the kidney when cDC1s were absent. Together, our data show that IRF8 is indispensable for kidney cDC1s. Kidney cDC1s mildly protect against post-ischemic AKI/AKD, probably via suppressing tissue inflammation and damage, which implies an immunoregulatory role for cDC1s.
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Affiliation(s)
- Na Li
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shen Zhen, China.,Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Stefanie Steiger
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Lingyan Fei
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shen Zhen, China
| | - Chenyu Li
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Chongxu Shi
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Natallia Salei
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany.,Institute for Cardiovascular Physiology and Pathophysiology, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Barbara U Schraml
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany.,Institute for Cardiovascular Physiology and Pathophysiology, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Zhihua Zheng
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shen Zhen, China
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Julia Lichtnekert
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
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35
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Ali R, Patel S, Hussain T. Angiotensin type 2 receptor activation limits kidney injury during the early phase and induces Treg cells during the late phase of renal ischemia. Am J Physiol Renal Physiol 2021; 320:F814-F825. [PMID: 33719572 PMCID: PMC8424555 DOI: 10.1152/ajprenal.00507.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 02/12/2021] [Accepted: 03/08/2021] [Indexed: 01/30/2023] Open
Abstract
Kidney infiltrating immune cells such as monocytes, neutrophils, and T cells play critical roles in renal ischemia-reperfusion (IR) injury and repair. Recently, the angiotensin II type 2 receptor (AT2R) has been implicated in protecting kidneys against injury and monocyte infiltration, particularly in chronic kidney disease. However, the role of AT2R in IR injury and repair phases and T cell modulation is unknown. To address this question, Sprague-Dawley rats were subjected to IR with or without AT2R agonist C21 treatment. IR caused early (2 h postreperfusion) renal functional injury (proteinuria, plasma urea, and creatinine) and enhanced immune cells (T cells and CD4 T cells) infiltration and levels of the proinflammatory cytokines monocyte chemoattractant protein-1, TNF-α, and IL-6. C21 treatment reversed these changes but increased the anti-inflammatory IL-10 level. On day 3, C21 treatment increased CD4+FoxP3+ (regulatory T cells) and CD4+IL-10+ cells and reduced kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in the kidney compared with the IR control, suggesting the involvement of AT2R in kidney repair. These data indicate that AT2R activation protects the kidney against IR injury and immune cell infiltration in the early phase and modulates CD4 T cells toward the regulatory T cell phenotype, which may have long-term beneficial effects on kidney function.NEW & NOTEWORTHY The angiotensin II type 2 receptor agonist C21 has been known to have a renoprotective role in various kidney pathologies. C21 treatment (before renal ischemia) attenuated postischemic kidney injury, kidney dysfunction, and immune cell infiltration during the injury phase. Also, C21 treatment modulated the kidney microenvironment by enhancing anti-inflammatory responses mainly mediated by IL-10. During the repair phase, C21 treatment enhanced IL-10-secreting CD4 T cells and FoxP3-secreting regulatory T cells in Sprague-Dawley rats.
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MESH Headings
- Acute Kidney Injury/immunology
- Acute Kidney Injury/metabolism
- Acute Kidney Injury/pathology
- Acute Kidney Injury/prevention & control
- Animals
- Anti-Inflammatory Agents/pharmacology
- Chemotaxis, Leukocyte/drug effects
- Cytokines/metabolism
- Disease Models, Animal
- Kidney/drug effects
- Kidney/immunology
- Kidney/metabolism
- Kidney/pathology
- Phenotype
- Rats, Sprague-Dawley
- Receptor, Angiotensin, Type 2/agonists
- Receptor, Angiotensin, Type 2/metabolism
- Reperfusion Injury/immunology
- Reperfusion Injury/metabolism
- Reperfusion Injury/pathology
- Reperfusion Injury/prevention & control
- Signal Transduction
- Sulfonamides/pharmacology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Thiophenes/pharmacology
- Time Factors
- Rats
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Affiliation(s)
- Riyasat Ali
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Sanket Patel
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Tahir Hussain
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
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Anders HJ, Wilkens L, Schraml B, Marschner J. One concept does not fit all: the immune system in different forms of acute kidney injury. Nephrol Dial Transplant 2021; 36:29-38. [PMID: 32337558 DOI: 10.1093/ndt/gfaa056] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Indexed: 02/06/2023] Open
Abstract
Renal and immune systems maintain body homoeostasis during physiological fluctuations and following tissue injury. The immune system plays a central role during acute kidney injury (AKI), adapting evolutional systems programmed for host defence and minimizing unnecessary collateral damage. Indeed, depending upon the disease context, the impact of the immune system upon the manifestations and consequences of AKI can be quite different. Here we provide an overview of the known and unknown involvement of the immune system within the wide range of different forms of AKI, to oppose oversimplification and to endorse deeper insights into the pathogenesis of the different diseases causing kidney injury. This approach may help to overcome some of the current hurdles in translational AKI research and the development of specific treatments for the different diseases, all presenting with an acute increase in serum creatinine or decline in urinary output. One concept does not fit all.
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Affiliation(s)
- Hans-Joachim Anders
- Department of Medicine IV, Renal Division, University Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Louise Wilkens
- Department of Medicine IV, Renal Division, University Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Barbara Schraml
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Planegg-Martinsried, Germany.,Faculty of Medicine, Institute for Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, Planegg-Martinsried, Germany
| | - Julian Marschner
- Department of Medicine IV, Renal Division, University Hospital of the Ludwig Maximilians University, Munich, Germany
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37
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Habib R. Multifaceted roles of Toll-like receptors in acute kidney injury. Heliyon 2021; 7:e06441. [PMID: 33732942 PMCID: PMC7944035 DOI: 10.1016/j.heliyon.2021.e06441] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/08/2020] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) in the first line defense system of our bodies; they are widely expressed on leukocytes and kidney epithelial cells. Infections due to pathogens or danger signals from injured tissues often activate several TLRs and these receptors mediate their signal transduction through the activation of transcription factors that regulate the expression of cytokine interleukin-1β (IL-1β), type I interferons (IFNs), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) dependent cytokines and chemokines. Acute kidney injury (AKI) involves early Toll-like receptors driven immunopathology, while resolution of inflammation is needed for rapid regeneration of injured tubular cells. Despite their well known function in the progression of inflammation; interestingly, activation of TLRs also has been implicated in renal epithelial repair through the induction of certain interleukins and improvement in autophagy mechanism. Studies have found that although the blockade of TLRs during the early injury phase of renal tissues prevented tubular necrosis, suppression of interleukins production and impaired kidney regeneration due to their blockade has been observed during the healing phase of tissue. Taken together, these results suggest that the two danger response programs of renal cells i.e. renal inflammation and regeneration may link at the level of TLRs. This review aims to emphasize on the role of TLRs signaling in different acute kidney injury phases. Understanding of these pathways may turn out to be effective as therapeutic option for kidney diseases.
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Affiliation(s)
- Rakhshinda Habib
- Dow Research Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences, Karachi, 74200, Pakistan
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38
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Cai J, McKinley T, Billiar I, Zenati MS, Gaski G, Vodovotz Y, Gruen DS, Billiar TR, Namas RA. Protective/reparative cytokines are suppressed at high injury severity in human trauma. Trauma Surg Acute Care Open 2021; 6:e000619. [PMID: 33748428 PMCID: PMC7929818 DOI: 10.1136/tsaco-2020-000619] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/04/2021] [Accepted: 02/06/2021] [Indexed: 01/03/2023] Open
Abstract
Background Trauma elicits a complex inflammatory response that, among multiple presenting factors, is greatly impacted by the magnitude of injury severity. Herein, we compared the changes in circulating levels of mediators with known proinflammatory roles to those with known protective/reparative actions as a function of injury severity in injured humans. Methods Clinical and biobank data were obtained from 472 (trauma database-1 (TD-1), University of Pittsburgh) and 89 (trauma database-2 (TD-2), Indiana University) trauma patients admitted to the intensive care unit (ICU) and who survived to discharge. Injury severity was estimated based on the Injury Severity Score (ISS), and this was used as both a continuous variable and for the purpose of grouping patients into severity-based cohorts. Samples within the first 24 hours were obtained from all patients and then daily up to day 7 postinjury in TD-1. Sixteen cytokines were assayed using Luminex and were analyzed using two-way analysis of variance (p<0.05). Results Patients with higher ISSs had longer ICU and hospital stays, days on mechanical ventilation and higher rates of nosocomial infection when compared with the mild and moderate groups. Time course analysis and correlations with ISS showed that 11 inflammatory mediators correlated positively with injury severity, consistent with previous reports. However, five mediators (interleukin (IL)-9, IL-21, IL-22, IL-23 and IL-17E/25) were suppressed in patients with high ISS and inversely correlated with ISS. Discussion These findings suggest that severe injury is associated with a suppression of a subset of cytokines known to be involved in tissue protection and regeneration (IL-9, IL-22 and IL-17E/25) and lymphocyte differentiation (IL-21 and IL-23), which in turn correlates with adverse clinical outcomes. Thus, patterns of proinflammatory versus protective/reparative mediators diverge with increasing ISS.
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Affiliation(s)
- Jinman Cai
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Todd McKinley
- Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Isabel Billiar
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mazen S Zenati
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Greg Gaski
- Department of Orthopedic Surgery, Inova Fairfax Medical Campus, Falls Church, Virginia, USA
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Center for Inflammation and Regenerative Modeling, University of Pittsburgh McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
| | - Danielle S Gruen
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Center for Inflammation and Regenerative Modeling, University of Pittsburgh McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
| | - Rami A Namas
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Center for Inflammation and Regenerative Modeling, University of Pittsburgh McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
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39
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Ludes PO, de Roquetaillade C, Chousterman BG, Pottecher J, Mebazaa A. Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery. Front Immunol 2021; 12:606622. [PMID: 33732235 PMCID: PMC7957065 DOI: 10.3389/fimmu.2021.606622] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.
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Affiliation(s)
- Pierre-Olivier Ludes
- Department of Anesthesiology and Intensive Care, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,EA 3072, Mitochondrie Stress Oxydant et Protection Musculaire, Faculté de Médecine, FRU 6702, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Charles de Roquetaillade
- Department of Anesthesiology and Critical Care, Hôpital Lariboisière, DMU Parabol, APHP.Nord, Paris, France.,Inserm U942 MASCOT, Université de Paris, Paris, France
| | - Benjamin Glenn Chousterman
- Department of Anesthesiology and Critical Care, Hôpital Lariboisière, DMU Parabol, APHP.Nord, Paris, France.,Inserm U942 MASCOT, Université de Paris, Paris, France
| | - Julien Pottecher
- Department of Anesthesiology and Intensive Care, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,EA 3072, Mitochondrie Stress Oxydant et Protection Musculaire, Faculté de Médecine, FRU 6702, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Alexandre Mebazaa
- Department of Anesthesiology and Critical Care, Hôpital Lariboisière, DMU Parabol, APHP.Nord, Paris, France.,Inserm U942 MASCOT, Université de Paris, Paris, France
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40
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Chen W, Shen Y, Fan J, Zeng X, Zhang X, Luan J, Wang Y, Zhang J, Fang S, Mei X, Zhao Z, Ju D. IL-22-mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury. Clin Transl Med 2021; 11:e324. [PMID: 33634980 PMCID: PMC7901723 DOI: 10.1002/ctm2.324] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/24/2021] [Accepted: 01/27/2021] [Indexed: 12/25/2022] Open
Abstract
Kidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin-22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here, we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin-induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidneys and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.
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Affiliation(s)
- Wei Chen
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
- Department of OphthalmologyStanford University School of MedicinePalo AltoCaliforniaUSA
| | - Yilan Shen
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
- Changhai HospitalSecond Military Medical UniversityShanghaiP. R. China
- Department of NephrologyShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiP. R. China
| | - Jiajun Fan
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
| | - Xian Zeng
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
| | - Xuyao Zhang
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
| | - Jingyun Luan
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
| | - Yichen Wang
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
| | - Jinghui Zhang
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
- Changhai HospitalSecond Military Medical UniversityShanghaiP. R. China
| | - Si Fang
- Tongcheng Hospital of Traditional Chinese MedicineAnhuiP. R. China
| | - Xiaobin Mei
- Changhai HospitalSecond Military Medical UniversityShanghaiP. R. China
| | - Zhen Zhao
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
| | - Dianwen Ju
- School of Pharmacy and Minhang HospitalShanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghaiP. R. China
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41
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Shen Y, Chen W, Han L, Bian Q, Fan J, Cao Z, Jin X, Ding T, Xian Z, Guo Z, Zhang W, Ju D, Mei X. VEGF-B antibody and interleukin-22 fusion protein ameliorates diabetic nephropathy through inhibiting lipid accumulation and inflammatory responses. Acta Pharm Sin B 2021; 11:127-142. [PMID: 33532185 PMCID: PMC7838033 DOI: 10.1016/j.apsb.2020.07.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/13/2020] [Accepted: 07/02/2020] [Indexed: 01/17/2023] Open
Abstract
Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.
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Key Words
- ACR, urine albumin-to-creatinine ratio
- ADFP, adipocyte differentiation-related protein
- AGEs, advanced glycation end products
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BUN, blood urea nitrogen
- Ccr, creatinine clearance rate
- DN, diabetic nephropathy
- Diabetic nephropathy
- ECM, extracellular matrix
- ESRD, end-stage renal disease
- FA, fatty acid
- FATPs, fatty acid transport proteins
- Fusion protein
- GBM, glomerular basement membrane
- GSEA, gene set enrichment analysis
- H&E, hematoxylin & eosin
- HbA1c%, glycosylated hemoglobin
- IL-22, interleukin-22
- Interleukin-22
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- NAC, N-acetyl-l-cysteine
- NLRP3, NOD-like receptor family pyrin domain-containing protein 3
- NRP-1, neuropilin-1
- PAS, periodic acid-Schiff
- ROS, reactive oxygen species
- SDS-PAGE, SDS-polyacrylamide gel electrophoresis
- TEM, transmission electron microscopy
- VEGF-B, vascular endothelial growth factor B
- VEGFR, vascular endothelial growth factor receptor
- Vascular endothelial growth factor B
- eGFR, estimated glomerular filtration rate
- β2-MG, β2 microglobulin
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Affiliation(s)
- Yilan Shen
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Wei Chen
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Lei Han
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Qi Bian
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jiajun Fan
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Zhonglian Cao
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Xin Jin
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Tao Ding
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zongshu Xian
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
| | - Zhiyong Guo
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Wei Zhang
- Department of Nephrology, Shanghai Yangpu Hospital of TCM, Shanghai 200090, China
| | - Dianwen Ju
- Department of Biological Medicines, Fudan University School of Pharmacy, Shanghai 201203, China
- Corresponding authors. Tel.: +86 21 31161407 (Xiaobin Mei), +86 21 51980037 (Dianwen Ju).
| | - Xiaobin Mei
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
- Corresponding authors. Tel.: +86 21 31161407 (Xiaobin Mei), +86 21 51980037 (Dianwen Ju).
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Ren Q, Cheng L, Yi J, Ma L, Pan J, Gou SJ, Fu P. Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases. Curr Med Chem 2020; 27:5829-5854. [PMID: 31161985 DOI: 10.2174/0929867325666190603110907] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/15/2019] [Accepted: 05/13/2019] [Indexed: 02/08/2023]
Abstract
Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.
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Affiliation(s)
- Qian Ren
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lu Cheng
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Yi
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Pan
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shen-Ju Gou
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ping Fu
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
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Combination of Alcohol and EVOH as a New Embolic Agent: Midterm Tissue and Inflammatory Effects in a Swine Model. Radiol Res Pract 2020; 2020:8831060. [PMID: 33163232 PMCID: PMC7605951 DOI: 10.1155/2020/8831060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/06/2020] [Accepted: 10/13/2020] [Indexed: 11/17/2022] Open
Abstract
Objective To evaluate the vascular occlusion and midterm tissue toxicity properties of a combination of ethylene-vinyl alcohol (EVOH) (Squid 18®) (75%) and alcohol (25%)—Alco-Squid 18—in a swine model. Materials and Methods Alco-Squid 18 (75% Squid 18® mixed with 25% alcohol) (AS18) was compared to embolization with 96% alcohol alone and to embolization with Squid 18® (S18®) alone. An arteriovenous malformation (AVM) model was created in group 1 (n = 2). Each AVM model was then embolized with AS18 or S18® alone with evaluation of a ratio between the volume of embolic agent divided by the volume of the AVM (evaluated by CT). For group 2 (n = 5), each agent was tested on three different kidneys (upper pole kidney artery). Pre- and postinterventional CTs, angiographies, blood alcohol content dosages, and histological studies (3 months postintervention) were performed. Results AS18 has better distal distribution than S18® alone, both in the kidneys (mean capsule-S18® distance: 3.9 mm (±0.23) and mean capsule-AS18 distance: 2.3 mm (±0.11) (p=0.029) and in the AVM model. Histological exploration found a higher rate of tubular necrosis with AS18 compared with S18® alone and alcohol alone (3.78 ± 0.44 compared to 2.33 ± 1.22 (p = 0.012) and 1.22 ± 0.67 (p < 0 .0001)). The blood alcohol content was negligible in all cases. Conclusion AS18 can suggest a better distal sclerotic and embolic character as compared with S18® alone without systemic toxicity.
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Tang R, Xiao X, Lu Y, Li H, Zhou Q, Kwadwo Nuro-Gyina P, Li X. Interleukin-22 attenuates renal tubular cells inflammation and fibrosis induced by TGF-β1 through Notch1 signaling pathway. Ren Fail 2020; 42:381-390. [PMID: 32338120 PMCID: PMC7241524 DOI: 10.1080/0886022x.2020.1753538] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/25/2020] [Accepted: 04/02/2020] [Indexed: 12/23/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1) is a crucial factor implicated in the development of renal inflammation and tubulointerstitial fibrosis (TIF). The cytokine interleukin 22 (IL-22) was previously reported to involve in the pathogenesis of chronic inflammatory diseases, however recent studies showed that IL-22 could reduced inflammatory responses and tissue damage. In the present study, we aim to investigate the role and mechanisms of IL-22 in renal tubular cells inflammation and fibrosis induced by TGF-β1. HK-2 cells were treated with TGF-β1 in the presence of IL-22 or the Notch pathway inhibitor dibenzazepine (DBZ) for 48 h. Collagen I (Col I), fibronectin (FN), α-smooth muscle actin (α-SMA), vimentin and E-Cadherin were detected by western blot, proinflammatory factors (TNF-α, IL-6) and chemokines (MCP-1, RANTES) were evaluated by ELISA. Jagged1, Notch1, NICD1, and Hes1 were also detected by western blot. We found TGF-β1 increased the levels of Col I, FN, α-SMA and vimentin in HK-2 cells compared with control, and decreased E-Cadherin level, however, IL-22 restored their expressions partly. IL-22 reduced overexpression of proinflammatory factors (TNF-α, IL-6) and chemokines (MCP-1, RANTES) levels induced by TGF-β1, along with down-regulation of Jagged1, Notch, NICD1 and Hes1. Fibrosis and inflammation in renal tubular cells induced by TGF-β1 could be attenuated by IL-22, and the effects were similar to DBZ treatment. Collectively, our study shows that IL-22 exerts a protective role in renal fibrotic and inflammatory responses induced by TGF-β1 in vitro, which may be through inhibiting Jagged1/Notch1 signaling pathway activation.
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Affiliation(s)
- Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiangcheng Xiao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang Lu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Huihui Li
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiaoling Zhou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | | | - Xia Li
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
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45
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Lissner MM, Cumnock K, Davis NM, Vilches-Moure JG, Basak P, Navarrete DJ, Allen JA, Schneider D. Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury. eLife 2020; 9:60165. [PMID: 33021470 PMCID: PMC7538157 DOI: 10.7554/elife.60165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.
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Affiliation(s)
- Michelle M Lissner
- Department of Microbiology and Immunology, Stanford University, Stanford, United States
| | - Katherine Cumnock
- Department of Microbiology and Immunology, Stanford University, Stanford, United States
| | - Nicole M Davis
- Department of Microbiology and Immunology, Stanford University, Stanford, United States
| | - José G Vilches-Moure
- Department of Comparative Medicine, Stanford University, Stanford, United States
| | - Priyanka Basak
- Department of Microbiology and Immunology, Stanford University, Stanford, United States
| | - Daniel J Navarrete
- Department of Microbiology and Immunology, Stanford University, Stanford, United States
| | - Jessica A Allen
- Division of Health, Mathematics and Science, Columbia College, Columbia, United States
| | - David Schneider
- Department of Microbiology and Immunology, Stanford University, Stanford, United States
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46
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Arshad T, Mansur F, Palek R, Manzoor S, Liska V. A Double Edged Sword Role of Interleukin-22 in Wound Healing and Tissue Regeneration. Front Immunol 2020; 11:2148. [PMID: 33042126 PMCID: PMC7527413 DOI: 10.3389/fimmu.2020.02148] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/07/2020] [Indexed: 12/14/2022] Open
Abstract
Wound healing and tissue regeneration is an intricate biological process that involves repair of cellular damage and maintenance of tissue integrity. Cascades involved in wound healing and tissue regeneration highly overlap with cancer causing pathways. Usually, subsequent tissue damage events include release of a number of cytokines to accomplish post-trauma restoration. IL-22 is one of the cytokines that are immediately produced to initiate immune response against several tissue impairments. IL-22 is a fundamental mediator in inflammation, mucous production, protective role against pathogens, wound healing, and tissue regeneration. However, accumulating evidence suggests pivotal role of IL-22 in instigation of various cancers due to its pro-inflammatory and tissue repairing activity. In this review, we summarize how healing effects of IL-22, when executed in an uncontrollable fashion can lead to carcinogenesis.
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Affiliation(s)
- Tanzeela Arshad
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Fizzah Mansur
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Richard Palek
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Sobia Manzoor
- Molecular Virology and Immunology Research Group, Atta-ur-Rahman School of Applied Bio-Sciences, National University of Sciences and Technology, Islamabad, Pakistan
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
| | - Vaclav Liska
- Department of Surgery, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czechia
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Strubl S, Torres JA, Spindt AK, Pellegrini H, Liebau MC, Weimbs T. STAT signaling in polycystic kidney disease. Cell Signal 2020; 72:109639. [PMID: 32325185 PMCID: PMC7269822 DOI: 10.1016/j.cellsig.2020.109639] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
The most common form of polycystic kidney disease (PKD) in humans is caused by mutations in the PKD1 gene coding for polycystin1 (PC1). Among the many identified or proposed functions of PC1 is its ability to regulate the activity of transcription factors of the STAT family. Most STAT proteins that have been investigated were found to be aberrantly activated in kidneys in PKD, and some have been shown to be drivers of disease progression. In this review, we focus on the role of signal transducer and activator of transcription (STAT) signaling pathways in various renal cell types in healthy kidneys as compared to polycystic kidneys, on the mechanisms of STAT regulation by PC1 and other factors, and on the possibility to target STAT signaling for PKD therapy.
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Affiliation(s)
- Sebastian Strubl
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA; Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jacob A Torres
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Alison K Spindt
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Hannah Pellegrini
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Max C Liebau
- Department of Pediatrics and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Weimbs
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA.
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Zhong Y, Tang R, Lu Y, Wang W, Xiao C, Meng T, Ao X, Li X, Peng L, Kwadwo Nuro-Gyina P, Zhou Q. Irbesartan may relieve renal injury by suppressing Th22 cells chemotaxis and infiltration in Ang II-induced hypertension. Int Immunopharmacol 2020; 87:106789. [PMID: 32683300 DOI: 10.1016/j.intimp.2020.106789] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/03/2020] [Accepted: 07/05/2020] [Indexed: 02/06/2023]
Abstract
Angiotensin II (Ang II) as an important pathogenic factor, has been implicated in the pathogenesis of hypertension and associated renal injury, and inhibition of Ang II can reduce renal inflammation and exert renal protective effects. In the present study, we determine the infiltration of Th22 cells in kidney and serum IL-22 level in hypertensive renal injury, and explore the effects and mechanisms of a widely used angiotensin II type 1 receptor blocker irbesartan on Th22 cells infiltration and related renal injury. Hypertension was induced by administering 1.5 mg/kg Ang II subcutaneously daily in C57BL/6 mice for 28 days. The mice were additionally treated by irbesartan or amlodipine. Renal Th22 lymphocytes frequency was evaluated through flow cytometry, serum IL-22 was detected by ELISA, and renal histopathological changes were also detected. The levels of renal chemokines (CCL20, CCL22, CCL27) and serum proinflammatory factors (IL-1β, IL-6, TNF-α) were measured by ELISA. Renal expression of alpha-smooth muscle actin (α-SMA), Fibronectin (FN) and collagen I (Col I) were evaluated by western blot. Chemotaxis assay and co-culture assay were conducted to clarify the effect of irbesartan on Th22 cells chemotaxis and differentiation in vitro. Our results showed in Ang II-infused hypertension mice, irbesartan suppressed renal Th22 cells accumulation as well as CCL20, CCL22, CCL27 expression. Serum IL-22, IL-1β, IL-6 and TNF-α concentrations wasere also reduced, in addition to inhibited renal expression of α-SMA, FN and Col I. Irbesartan treatment lowered blood pressure, urinary protein and renal pathological damage. In vitro, irbesartan could abrogate the Th22 cells chemotaxis and differentiation, compared to control and amlodipine groups. Our study reveals a new pharmacological mechanism that irbesartan ameliorates inflammation and fibrosis in hypertensive renal injury induced by Ang II, maybe through inhibiting Th22 cells chemotaxis and infiltration, which provides a new theoretical basis and therapeutic target for hypertensive renal injury.
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Affiliation(s)
- Yong Zhong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Yang Lu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Wang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chenggen Xiao
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ting Meng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang Ao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaozhao Li
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Peng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | | | - Qiaoling Zhou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China
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49
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Tammaro A, Kers J, Scantlebery AML, Florquin S. Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration. Front Immunol 2020; 11:1346. [PMID: 32733450 PMCID: PMC7358591 DOI: 10.3389/fimmu.2020.01346] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 05/27/2020] [Indexed: 01/10/2023] Open
Abstract
Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells (TECs). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and TEC repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra- and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that TEC-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides TECs with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within TECs, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in TECs: from programmed cell death (PCD) and mitochondrial dysfunction-mediated metabolic rewiring of TECs to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in TECs and their therapeutic potential in both experimental and clinical research.
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Affiliation(s)
- Alessandra Tammaro
- Department of Pathology, Amsterdam UMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands
| | - Jesper Kers
- Department of Pathology, Amsterdam UMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands.,Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.,Biomolecular Systems Analytics, Van 't Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Amsterdam, Netherlands
| | - Angelique M L Scantlebery
- Department of Pathology, Amsterdam UMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands
| | - Sandrine Florquin
- Department of Pathology, Amsterdam UMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands.,Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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50
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Ingersoll MA, Starkey MR. Interleukin-22 in urinary tract disease - new experimental directions. Clin Transl Immunology 2020; 9:e1143. [PMID: 32523694 PMCID: PMC7276185 DOI: 10.1002/cti2.1143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 05/12/2020] [Indexed: 12/25/2022] Open
Affiliation(s)
- Molly A Ingersoll
- Department of Immunology Institut Pasteur Paris France.,INSERM U1223 Paris France
| | - Malcolm R Starkey
- Department of Immunology and Pathology Central Clinical School Monash University Melbourne VIC Australia.,Priority Research Centre GrowUpWell Faculty of Health and Medicine The University of Newcastle Callaghan NSW Australia
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