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Brooks AJ, Gallego-López MDC, De Miguel C. Endothelin-1 signaling in the kidney: recent advances and remaining gaps. Am J Physiol Renal Physiol 2025; 328:F815-F827. [PMID: 40272184 DOI: 10.1152/ajprenal.00304.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/22/2024] [Accepted: 04/21/2025] [Indexed: 04/25/2025] Open
Abstract
The involvement of endothelin-1 (ET-1) in the maintenance of kidney function as well as its role in renal pathophysiology has been appreciated for decades; however, there still exist important gaps in knowledge in our understanding of the mechanistic pathways activated by this system in the kidney. The purpose of this article is to review recent advances in the field, as well as to underscore areas that need more investigation, with an emphasis on the interplay of ET-1 with inflammation, sex differences, circadian rhythms of renal function, the most recent clinical trials involving the ET-1 system, and the interaction between microRNAs and the ET-1 system.
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Affiliation(s)
- Abigail J Brooks
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - María Del Carmen Gallego-López
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Department of Physiology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Carmen De Miguel
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
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Anyfanti P, Theodorakopoulou M, Iatridi F, Sarafidis P. Endothelin receptor antagonists for diabetic kidney disease: back to the future? Expert Opin Investig Drugs 2025; 34:317-327. [PMID: 40313198 DOI: 10.1080/13543784.2025.2500294] [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: 01/29/2025] [Accepted: 04/17/2025] [Indexed: 05/03/2025]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide. Endothelin-1 (ET-1) is a potent vasoconstrictor secreted by vascular endothelial cells, actively involved in the pathophysiology of numerous cardiovascular diseases. Based on the differential downstream effects of ET-1 binding to its two distinct types of receptors (ETA/ETB) within the kidney, selective ETA receptor blockade has been long proposed as a promising treatment modality for DKD. AREAS COVERED This review aims to examine the available evidence base for the use of ERAs in the treatment of DKD, by critically reappraising available landmark trials and discussing their possible position in the context of current treatment of this disease. EXPERT OPINION Despite early enthusiasm and widespread expectations, endothelin receptor antagonists (ERAs) faded into obscurity following the release of the first randomized controlled trials (RCTs). More recent RCTs using different compounds have re-introduced ERAs as a promising treatment in the growing pharmaceutical armamentarium of DKD. While the future of DKD management will be based on a more personalized approach, new, robust evidence from appropriately designed RCTs is eagerly anticipated to clearly define the role of ERAs in DKD.
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Affiliation(s)
- Panagiota Anyfanti
- Third Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta Theodorakopoulou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fotini Iatridi
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis Sarafidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Smeijer JD, Kohan DE, Dhaun N, Noronha IL, Liew A, Heerspink HJL. Endothelin receptor antagonists in chronic kidney disease. Nat Rev Nephrol 2025; 21:175-188. [PMID: 39643698 DOI: 10.1038/s41581-024-00908-z] [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: 10/30/2024] [Indexed: 12/09/2024]
Abstract
Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETA receptor and angiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.
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Affiliation(s)
- J David Smeijer
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City, UT, USA
| | - Neeraj Dhaun
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Irene L Noronha
- Division of Nephrology, University of Sao Paulo Medical School, Sao Paulo, Brazil
- George Institute for Global Health, Sydney, New South Wales, Australia
| | - Adrian Liew
- George Institute for Global Health, Sydney, New South Wales, Australia
- Mount Elizabeth Novena Hospital, Singapore, Singapore
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
- George Institute for Global Health, Sydney, New South Wales, Australia.
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Gu Y, Yu S, Gu W, Li B, Xue J, Liu J, Zhang Q, Yin Y, Zhang H, Guo Q, Yuan M, Lyu Z, Mu Y, Cheng Y. M2 macrophage infusion ameliorates diabetic glomerulopathy via the JAK2/STAT3 pathway in db/db mice. Ren Fail 2024; 46:2378210. [PMID: 39090966 PMCID: PMC11299449 DOI: 10.1080/0886022x.2024.2378210] [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: 03/20/2024] [Revised: 07/02/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
Objectives: To explore the therapeutic effects of M2 macrophages in diabetic nephropathy (DN) and their mechanism.Methods: We infused M2 macrophages stimulated with IL-4 into 10-week-old db/db mice once a week for 4 weeks through the tail vein as M2 group. Then we investigated the role of M2 macrophages in alleviating the infammation of DN and explored the mechanism.Results: M2 macrophages hindered the progression of DN, reduced the levels of IL-1β (DN group was 34%, M2 group was 13%, p < 0.01) and MCP-1 (DN group was 49%, M2 group was 16%, p < 0.01) in the glomeruli. It was also proven that M2 macrophages alleviate mesangial cell injury caused by a high glucose environment. M2 macrophage tracking showed that the infused M2 macrophages migrated to the kidney, and the number of M2 macrophages in the kidney reached a maximum on day 3. Moreover, the ratio of M2 to M1 macrophages was 2.3 in the M2 infusion group, while 0.4 in the DN group (p < 0.01). Mechanistically, M2 macrophages downregulated Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 in mesangial cells.Conclusions: Multiple infusions of M2 macrophages significantly alleviated inflammation in the kidney and hindered the progression of DN at least partially by abrogating the M1/M2 homeostasis disturbances and suppressing the JAK2/STAT3 pathway in glomerular mesangial cells. M2 macrophage infusion may be a new therapeutic strategy for DN treatment.
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Affiliation(s)
- Yulin Gu
- Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Songyan Yu
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Bing Li
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Jing Xue
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Jiejie Liu
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, Beijing, China
| | - Qi Zhang
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Haixia Zhang
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Qinghua Guo
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Mingxia Yuan
- Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhaohui Lyu
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Yiming Mu
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Yu Cheng
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
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Kohan DE, Bedard P, Jenkinson C, Hendry B, Komers R. Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease. Clin Sci (Lond) 2024; 138:645-662. [PMID: 38808486 PMCID: PMC11139641 DOI: 10.1042/cs20240249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/30/2024]
Abstract
Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.
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Affiliation(s)
- Donald E. Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City, UT, U.S.A
| | | | | | - Bruce Hendry
- Travere Therapeutics, Inc., San Diego, CA, U.S.A
| | - Radko Komers
- Travere Therapeutics, Inc., San Diego, CA, U.S.A
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Terzo C, Gembillo G, Cernaro V, Longhitano E, Calabrese V, Casuscelli C, Peritore L, Santoro D. Investigational new drugs for the treatment of chronic renal failure: an overview of the literature. Expert Opin Investig Drugs 2024; 33:319-334. [PMID: 38429874 DOI: 10.1080/13543784.2024.2326624] [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: 10/08/2023] [Accepted: 02/29/2024] [Indexed: 03/03/2024]
Abstract
INTRODUCTION Chronic kidney disease (CKD) is widespread throughout the world, with a high social and health impact. It is considered a 'silent killer' for its sudden onset without symptoms in the early stages of the disease. The main goal of nephrologists is to slow the progression of kidney disease and treat the associated symptoms with a range of new medications. AREAS COVERED The aim of this systematic review is to analyze the new investigational drugs for the treatment of chronic renal failure. Data were obtained from the available scientific literature and from the ClinicalTrials.gov website. EXPERT OPINION Among the drugs currently being researched, SGLT2 inhibitors appear to be the most promising drugs for the treatment of CKD, has they have slower progression of CKD and protection of cardiorenal function. An important role in the future of CKD treatment is played by autologous cell-therapy, which appears to be a new frontier in the treatment of CKD. Other therapeutic strategies are currently being investigated and have been shown to slow the progression of CKD. However, further studies are needed to determine whether these approaches may offer benefits in slowing the progression of CKD in the near future.
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Affiliation(s)
- Chiara Terzo
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Guido Gembillo
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Valeria Cernaro
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Elisa Longhitano
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Vincenzo Calabrese
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Chiara Casuscelli
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Luigi Peritore
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
| | - Domenico Santoro
- Department of Clinical and Experimental Medicine, University of Messina, AOU G. Martino PAD B, Messina, Italy
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Mohamed R, Sullivan JC. Sustained activation of 12/15 lipoxygenase (12/15 LOX) contributes to impaired renal recovery post ischemic injury in male SHR compared to females. Mol Med 2023; 29:163. [PMID: 38049738 PMCID: PMC10696802 DOI: 10.1186/s10020-023-00762-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 11/19/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females. METHODS 13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography-mass spectrometry (LC/MS). RESULTS Male SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR. CONCLUSION Our data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.
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Affiliation(s)
- Riyaz Mohamed
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, 30912, United States.
| | - Jennifer C Sullivan
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, 30912, United States
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Veenit V, Heerspink HJL, Ahlström C, Greasley PJ, Skritic S, van Zuydam N, Kohan DE, Hansen PBL, Menzies RI. The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan. Nephrol Dial Transplant 2023; 38:2289-2297. [PMID: 37102226 PMCID: PMC10539223 DOI: 10.1093/ndt/gfad078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Endothelin A receptor antagonists (ETARA) slow chronic kidney disease (CKD) progression but their use is limited due to fluid retention and associated clinical risks. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) cause osmotic diuresis and improve clinical outcomes in CKD and heart failure. We hypothesized that co-administration of the SGLT2i dapagliflozin with the ETARA zibotentan would mitigate the fluid retention risk using hematocrit (Hct) and bodyweight as proxies for fluid retention. METHODS Experiments were performed in 4% salt fed WKY rats. First, we determined the effect of zibotentan (30, 100 or 300 mg/kg/day) on Hct and bodyweight. Second, we assessed the effect of zibotentan (30 or 100 mg/kg/day) alone or in combination with dapagliflozin (3 mg/kg/day) on Hct and bodyweight. RESULTS Hct at Day 7 was lower in zibotentan versus vehicle groups [zibotentan 30 mg/kg/day, 43% (standard error 1); 100 mg/kg/day, 42% (1); and 300 mg/kg/day, 42% (1); vs vehicle, 46% (1); P < .05], while bodyweight was numerically higher in all zibotentan groups compared with vehicle. Combining zibotentan with dapagliflozin for 7 days prevented the change in Hct [zibotentan 100 mg/kg/day and dapagliflozin, 45% (1); vs vehicle 46% (1); P = .44] and prevented the zibotentan-driven increase in bodyweight (zibotentan 100 mg/kg/day + dapagliflozin 3 mg/kg/day = -3.65 g baseline corrected bodyweight change; P = .15). CONCLUSIONS Combining ETARA with SGLT2i prevents ETARA-induced fluid retention, supporting clinical studies to assess the efficacy and safety of combining zibotentan and dapagliflozin in individuals with CKD.
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Affiliation(s)
- Vandana Veenit
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Christine Ahlström
- DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter J Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Stanko Skritic
- Innovation Strategies & External Liaison, Pharmaceutical Technologies & Development, AstraZeneca, Gothenburg, Sweden; Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Natalie van Zuydam
- Biostatistics Sweden, Data Science and Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City, UT, USA
| | - Pernille B L Hansen
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Robert I Menzies
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Wada R, Kleijn HJ, Zhang L, Chen S. Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis. CPT Pharmacometrics Syst Pharmacol 2023; 12:1080-1092. [PMID: 37221817 PMCID: PMC10431048 DOI: 10.1002/psp4.12996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/17/2023] [Accepted: 05/03/2023] [Indexed: 05/25/2023] Open
Abstract
Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.
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Affiliation(s)
| | | | - Lu Zhang
- Certara, Inc.Menlo ParkCaliforniaUSA
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Zhang K, Fu Z, Zhang Y, Chen X, Cai G, Hong Q. The role of cellular crosstalk in the progression of diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:1173933. [PMID: 37538798 PMCID: PMC10395826 DOI: 10.3389/fendo.2023.1173933] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/26/2023] [Indexed: 08/05/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most common complications of diabetes, and its main manifestations are progressive proteinuria and abnormal renal function, which eventually develops end stage renal disease (ESRD). The pathogenesis of DN is complex and involves many signaling pathways and molecules, including metabolic disorders, genetic factors, oxidative stress, inflammation, and microcirculatory abnormalities strategies. With the development of medical experimental techniques, such as single-cell transcriptome sequencing and single-cell proteomics, the pathological alterations caused by kidney cell interactions have attracted more and more attention. Here, we reviewed the characteristics and related mechanisms of crosstalk among kidney cells podocytes, endothelial cells, mesangial cells, pericytes, and immune cells during the development and progression of DN and highlighted its potential therapeutic effects.
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Gao ZX, Wei QC, Shu TT, Li ST, Zhou R, Li MY, Mao ZH, Liu DW, Liu ZS, Wu P. Kir4.1 deletion prevents salt-sensitive hypertension in early streptozotocin-induced diabetic mice via Na + -Cl - cotransporter in the distal convoluted tubule. J Hypertens 2023; 41:958-970. [PMID: 37016934 DOI: 10.1097/hjh.0000000000003419] [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: 04/06/2023]
Abstract
OBJECTIVES Functional impairment of renal sodium handling and blood pressure (BP) homeostasis is an early characteristic manifestation of type 1 diabetes. However, the underlying mechanisms remain unclear. METHODS Metabolic cages, radio-telemetry, immunoblotting, and electrophysiology were utilized to examine effects of high salt (8% NaCl, HS) intake on Na + /K + balance, BP, Na + -Cl - cotransporter (NCC) function, and basolateral K + channel activity in the distal convoluted tubule (DCT) under diabetic conditions. RESULTS Improper Na + balance, hypernatremia, and a mild but significant increase in BP were found in streptozotocin (STZ)-induced diabetic mice in response to HS intake for 7 days. Compared to the vehicle, STZ mice showed increased Kir4.1 expression and activity in the DCT, a more negative membrane potential, higher NCC abundance, and enhanced hydrochlorothiazide-induced natriuretic effect. However, HS had no significant effect on basolateral Kir4.1 expression/activity and DCT membrane potential, or NCC activity under diabetic conditions, despite a downregulation in phosphorylated NCC abundance. In contrast, HS significantly downregulated the expression of Na + -H + exchanger 3 (NHE3) and cleaved epithelial sodium channel-γ in STZ mice, despite an increase in NHE3 abundance after STZ treatment. Kir4.1 deletion largely abolished STZ-induced upregulation of NCC expression and prevented BP elevation during HS intake. Interestingly, HS causes severe hypokalemia in STZ-treated kidney-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice and lead to death within a few days, which could be attributed to a higher circulating aldosterone level. CONCLUSIONS We concluded that Kir4.1 is required for upregulating NCC activity and may be essential for developing salt-sensitive hypertension in early STZ-induced diabetes.
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Affiliation(s)
- Zhong-Xiuzi Gao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Qi-Chao Wei
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Ting-Ting Shu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Shu-Ting Li
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Rui Zhou
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Ming-Yan Li
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zi-Hui Mao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dong-Wei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhang-Suo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Peng Wu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University
- Institute of Nephrology, Zhengzhou University
- Henan Province Clinical Research Center for Kidney Disease
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
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12
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Rayego-Mateos S, Rodrigues-Diez RR, Fernandez-Fernandez B, Mora-Fernández C, Marchant V, Donate-Correa J, Navarro-González JF, Ortiz A, Ruiz-Ortega M. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int 2023; 103:282-296. [PMID: 36470394 DOI: 10.1016/j.kint.2022.10.030] [Citation(s) in RCA: 122] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 10/05/2022] [Accepted: 10/31/2022] [Indexed: 12/07/2022]
Abstract
Diabetic kidney disease (DKD) is one of the fastest growing causes of chronic kidney disease and associated morbidity and mortality. Preclinical research has demonstrated the involvement of inflammation in its pathogenesis and in the progression of kidney damage, supporting clinical trials designed to explore anti-inflammatory strategies. However, the recent success of sodium-glucose cotransporter-2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone has changed both guidelines and standard of care, rendering obsolete older studies directly targeting inflammatory mediators and the clinical development was discontinued for most anti-inflammatory drugs undergoing clinical trials for DKD in 2016. Given the contribution of inflammation to the pathogenesis of DKD, we review the impact on kidney inflammation of the current standard of care, therapies undergoing clinical trials, or repositioned drugs for DKD. Moreover, we review recent advances in the molecular regulation of inflammation in DKD and discuss potential novel therapeutic strategies with clinical relevance. Finally, we provide a road map for future research aimed at integrating the growing knowledge on inflammation and DKD into clinical practice to foster improvement of patient outcomes.
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Affiliation(s)
- Sandra Rayego-Mateos
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Ricord2040, Instituto de Salud Carlos II, Spain
| | - Raul R Rodrigues-Diez
- Ricord2040, Instituto de Salud Carlos II, Spain; Translational Immunology, Instituto de Investigación Sanitaria del Principado de Asturias ISPA, Oviedo, Asturias, Spain
| | - Beatriz Fernandez-Fernandez
- Ricord2040, Instituto de Salud Carlos II, Spain; Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma, Madrid, Spain
| | - Carmen Mora-Fernández
- Ricord2040, Instituto de Salud Carlos II, Spain; Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Vanessa Marchant
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Ricord2040, Instituto de Salud Carlos II, Spain
| | - Javier Donate-Correa
- Ricord2040, Instituto de Salud Carlos II, Spain; Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Juan F Navarro-González
- Ricord2040, Instituto de Salud Carlos II, Spain; Research Unit, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Alberto Ortiz
- Ricord2040, Instituto de Salud Carlos II, Spain; Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma, Madrid, Spain
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Ricord2040, Instituto de Salud Carlos II, Spain.
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13
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Chan ATP, Tang SCW. Advances in the management of diabetic kidney disease: beyond sodium-glucose co-transporter 2 inhibitors. Kidney Res Clin Pract 2022; 41:682-698. [PMID: 35977903 PMCID: PMC9731775 DOI: 10.23876/j.krcp.21.285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/20/2022] [Accepted: 05/09/2022] [Indexed: 08/09/2023] Open
Abstract
Progress in the treatment of diabetic kidney disease (DKD) has been modest since the early trials on renin-angiotensin-aldosterone system inhibitors (RAASis). Although sodium-glucose co-transporter 2 inhibitors (SGLT2is) have revolutionized the management of DKD by lowering proteinuria and protecting organs, other novel treatment approaches with good evidence and efficacy that can be used in conjunction with a RAASi or SGLT2i in managing DKD have emerged in the past few years. This review discusses the evidence for glucagon-like peptide-1 receptor agonist, selective mineralocorticoid receptor antagonist, and selective endothelin A receptor antagonist, emerging treatment options for DKD beyond SGLT2 inhibition.
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Affiliation(s)
- Anthony T. P. Chan
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Sydney C. W. Tang
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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14
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Hsieh CC, Chang CC, Hsu YC, Lin CL. Immune Modulation by Myeloid-Derived Suppressor Cells in Diabetic Kidney Disease. Int J Mol Sci 2022; 23:13263. [PMID: 36362050 PMCID: PMC9655277 DOI: 10.3390/ijms232113263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/29/2022] [Accepted: 10/30/2022] [Indexed: 09/22/2023] Open
Abstract
Diabetic kidney disease (DKD) frequently leads to end-stage renal disease and other life-threatening illnesses. The dysregulation of glomerular cell types, including mesangial cells, endothelial cells, and podocytes, appears to play a vital role in the development of DKD. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory and anti-inflammatory properties through the depletion of L-arginine that is required by T cells, through generation of oxidative stress, interference with T-cell recruitment and viability, proliferation of regulatory T cells, and through the promotion of pro-tumorigenic functions. Under hyperglycemic conditions, mouse mesangial cells reportedly produce higher levels of fibronectin and pro-inflammatory cytokines. Moreover, the number of MDSCs is noticeably decreased, weakening inhibitory immune activities, and creating an inflammatory environment. In diabetic mice, immunotherapy with MDSCs that were induced by a combination of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1β, and IL-6, reduced kidney to body weight ratio, fibronectin expression, and fibronectin accumulation in renal glomeruli, thus ameliorating DKD. In conclusion, MDSCs exhibit anti-inflammatory activities that help improve renal fibrosis in diabetic mice. The therapeutic targeting of the proliferative or immunomodulatory pathways of MDSCs may represent an alternative immunotherapeutic strategy for DKD.
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Affiliation(s)
- Ching-Chuan Hsieh
- Division of General Surgery, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
| | - Cheng-Chih Chang
- Division of General Surgery, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
| | - Yung-Chien Hsu
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
- Division of Nephrology, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
| | - Chun-Liang Lin
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
- Division of Nephrology, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
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15
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Effects of Genistein on Common Kidney Diseases. Nutrients 2022; 14:nu14183768. [PMID: 36145144 PMCID: PMC9506319 DOI: 10.3390/nu14183768] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 12/16/2022] Open
Abstract
Genistein is a naturally occurring phytoestrogen (soy or soybean products) that is classified as an isoflavone, and its structure is similar to that of endogenous estrogens; therefore, genistein can exert an estrogen-like effect via estrogen receptors. Additionally, genistein is a tyrosine kinase inhibitor, which enables it to block abnormal cell growth and proliferation signals through the inhibition of tyrosine kinase. Genistein is also an angiogenesis inhibitor and an antioxidant. Genistein has effects on kidney cells, some of the kidney’s physiological functions, and a variety of kidney diseases. First, genistein exerts a protective effect on normal cells by reducing the inflammatory response, inhibiting apoptosis, inhibiting oxidative stress, inhibiting remodeling, etc., but after cell injury, the protective effect of genistein decreases or even has the opposite effect. Second, genistein can regulate renin intake to maintain blood pressure balance, regulate calcium uptake to regulate Ca2+ and Pi balances, and reduce vasodilation to promote diuresis. Third, genistein has beneficial effects on a variety of kidney diseases (including acute kidney disease, kidney cancer, and different chronic kidney diseases), such as reducing symptoms, delaying disease progression, and improving prognosis. Therefore, this paper reviews animal and human studies on the protective effects of genistein on the kidney in vivo and in vitro to provide a reference for clinical research in the future.
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16
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Persistent vascular congestion in male spontaneously hypertensive rats contributes to delayed recovery of renal function following ischemia-reperfusion compared to females. Clin Sci (Lond) 2022; 136:825-840. [PMID: 35535709 DOI: 10.1042/cs20220002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/27/2022] [Accepted: 05/09/2022] [Indexed: 11/17/2022]
Abstract
Acute kidney injury (AKI) is a serious and frequent clinical complication with mortality rates up to 80%. Vascular congestion in the renal outer medulla occurs early after ischemia reperfusion (IR) injury, and congestion has been linked to worsened outcomes following IR. There is evidence implicating both male sex and preexisting hypertension as risk factors for poor outcomes following IR. The present study tested the hypothesis that male spontaneously hypertensive rats (SHR) have greater vascular congestion and impaired renal recovery following renal IR vs. female SHR and normotensive male Sprague-Dawley rats (SD). 13 wk old male and female SHR and SD were subjected to sham surgery or 30 minutes of warm bilateral ischemia followed by reperfusion. Rats were euthanized 24 hours or 7 days post-IR. IR increased renal injury in all groups vs. sham controls at 24 hours. At 7 days post-IR, injury remained elevated only in male SHR. Histological examination of SD and SHR kidneys 24 hours post-IR showed vascular congestion in males and females. Vascular congestion was sustained only in male SHR 7 days post-IR. To assess the role of vascular congestion on impaired recovery following IR, additional male and female SHR were pretreated with heparin (200 U/kg) prior to IR. Heparin pre-treatment reduced IR-induced congestion and improved renal function in male SHR 7 days post-IR. Interestingly, preventing increases in BP in male SHR did not alter sustained vascular congestion. Our data demonstrate that IR-induced vascular congestion is a major driving factor for impaired renal recovery in male SHR.
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17
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Mitochondrial Pathophysiology on Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23031776. [PMID: 35163697 PMCID: PMC8836100 DOI: 10.3390/ijms23031776] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression.
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18
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Belanger KM, Mohamed R, Webb RC, Sullivan JC. Sex Differences in TLR4 Expression in SHR Do Not Contribute to Sex Differences in Blood Pressure or the Renal T cell Profile. Am J Physiol Regul Integr Comp Physiol 2022; 322:R319-R325. [PMID: 35107023 PMCID: PMC8917934 DOI: 10.1152/ajpregu.00237.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hypertension is a primary risk factor for the development of cardiovascular disease. Mechanisms controlling blood pressure (BP) in men and women are still being investigated, however, there is increasing evidence supporting a role for the innate immune system. Specifically, Toll-like receptors (TLR), and TLR4 in particular, have been implicated in the development of hypertension in male spontaneously hypertensive rats (SHR). Despite established sex differences in BP control and inflammatory markers in hypertensive males and females, little is known regarding the role of TLR4 in hypertension in females. Our hypotheses were that male SHR have greater TLR4 expression compared to females, and that sex differences in TLR4 contribute to sex differences in BP and the T cell profile. To test these hypotheses, initial studies measured renal TLR4 protein expression in 13-week old male and female SHR. Additional SHR were implanted with telemetry devices and randomized to treatment with either IgG or TLR4 neutralizing antibodies. Untreated control male SHR have greater TLR4 protein expression in the kidney compared to females. However, treatment with TLR4 neutralizing antibody for 2 weeks did not significantly alter BP in either male or female SHR. Interestingly, neutralization of TLR4 increased renal CD3+ T cells in female SHR, with no alteration in CD4+ T cells or CD8+ T cells in either sex. Taken together, our data indicates that although male SHR have greater renal TLR4 expression than females, TLR4 does not contribute to the higher BP and more pro-inflammatory renal T cell prolife in males vs. females.
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Affiliation(s)
- Kasey M Belanger
- Department of Physiology Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Riyaz Mohamed
- Department of Physiology Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - R Clinton Webb
- Department of Pharmacology, Physiology, and Neuroscience University of South Carolina, Columbia, South Carolina, United States
| | - Jennifer C Sullivan
- Department of Physiology Medical College of Georgia at Augusta University, Augusta, GA, United States
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19
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Peng L, Chen Y, Shi S, Wen H. Stem cell-derived and circulating exosomal microRNAs as new potential tools for diabetic nephropathy management. Stem Cell Res Ther 2022; 13:25. [PMID: 35073973 PMCID: PMC8785577 DOI: 10.1186/s13287-021-02696-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite major advances in the treatment of diabetic nephropathy (DN) in recent years, it remains the most common cause of end-stage renal disease. An early diagnosis and therapy may slow down the DN progression. Numerous potential biomarkers are currently being researched. Circulating levels of the kidney-released exosomes and biological molecules, which reflect the DN pathology including glomerular and tubular dysfunction as well as mesangial expansion and fibrosis, have shown the potential for predicting the occurrence and progression of DN. Moreover, many experimental therapies are currently being investigated, including stem cell therapy and medications targeting inflammatory, oxidant, or pro-fibrotic pathways activated during the DN progression. The therapeutic potential of stem cells is partly depending on their secretory capacity, particularly exosomal microRNAs (Exo-miRs). In recent years, a growing line of research has shown the participation of Exo-miRs in the pathophysiological processes of DN, which may provide effective therapeutic and biomarker tools for DN treatment. METHODS A systematic literature search was performed in MEDLINE, Scopus, and Google Scholar to collect published findings regarding therapeutic stem cell-derived Exo-miRs for DN treatment as well as circulating Exo-miRs as potential DN-associated biomarkers. FINDINGS Glomerular mesangial cells and podocytes are the most important culprits in the pathogenesis of DN and, thus, can be considered valuable therapeutic targets. Preclinical investigations have shown that stem cell-derived exosomes can exert beneficial effects in DN by transferring renoprotective miRs to the injured mesangial cells and podocytes. Of note, renoprotective Exo-miR-125a secreted by adipose-derived mesenchymal stem cells can improve the injured mesangial cells, while renoprotective Exo-miRs secreted by adipose-derived stem cells (Exo-miR-486 and Exo-miR-215-5p), human urine-derived stem cells (Exo-miR-16-5p), and bone marrow-derived mesenchymal stem cells (Exo-miR-let-7a) can improve the injured podocytes. On the other hand, clinical investigations have indicated that circulating Exo-miRs isolated from urine or serum hold great potential as promising biomarkers in DN.
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Affiliation(s)
- Lei Peng
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Yu Chen
- Department of Cardiology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Shaoqing Shi
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
| | - Heling Wen
- Department of Cardiology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, 610072, China.
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20
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Neder TH, Schrankl J, Fuchs MAA, Broeker KAE, Wagner C. Endothelin receptors in renal interstitial cells do not contribute to the development of fibrosis during experimental kidney disease. Pflugers Arch 2021; 473:1667-1683. [PMID: 34355294 PMCID: PMC8433107 DOI: 10.1007/s00424-021-02604-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/24/2021] [Accepted: 07/01/2021] [Indexed: 11/26/2022]
Abstract
Renal interstitial fibrosis is characterized by the development of myofibroblasts, originating from resident renal and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various factors. Among these, endothelins have been discussed as potential modulators of renal fibrosis. Utilizing mouse models of adenine nephropathy (AN) and unilateral ureter occlusion (UUO), this study aimed to investigate the contribution of endothelin signaling in stromal mesenchymal resident renal interstitial cells. We found in controls that adenine feeding and UUO caused marked upregulations of endothelin-1 (ET-1) gene expression in endothelial and in tubular cells and a strong upregulation of ETA-receptor (ETA-R) gene expression in interstitial and mesangial cells, while the gene expression of ETB-receptor (ETB-R) did not change. Conditional deletion of ETA-R and ETB-R gene expression in the FoxD1 stromal cell compartment which includes interstitial cells significantly reduced renal ETA-R gene expression and moderately lowered renal ETB-R gene expression. ET receptor (ET-R) deletion exerted no apparent effects on kidney development nor on kidney function. Adenine feeding and UUO led to similar increases in profibrotic and proinflammatory gene expression in control as well as in ETAflflETBflfl FoxD1Cre+ mice (ET-Ko). In summary, our findings suggest that adenine feeding and UUO activate endothelin signaling in interstitial cells which is due to upregulated ETA-R expression and enhanced renal ET-1 production Our data also suggest that the activation of endothelin signaling in interstitial cells has less impact for the development of experimentally induced fibrosis.
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Affiliation(s)
- Thomas H Neder
- Institute of Physiology, University of Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany
| | - Julia Schrankl
- Institute of Physiology, University of Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany
| | - Michaela A A Fuchs
- Institute of Physiology, University of Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany
| | - Katharina A E Broeker
- Institute of Physiology, University of Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany
| | - Charlotte Wagner
- Institute of Physiology, University of Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany.
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21
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Diabetic nephropathy: A twisted thread to unravel. Life Sci 2021; 278:119635. [PMID: 34015285 DOI: 10.1016/j.lfs.2021.119635] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/18/2022]
Abstract
Diabetic nephropathy (DN), a persistent microvascular problem of diabetes mellitus is described as an elevated level of albumin excretion in urine and impaired renal activity. The morbidity and mortality of type-1 diabetics and type-2 diabetics due to end stage renal disease is also a result of the increased prevalence of DN. DN typically occurs as a consequence of an association among metabolic and hemodynamic variables, activating specific pathways leading to renal injury. According to current interventions, intensive glucose regulation decreases the threat of DN incidence and growth, and also suppressing the renin-angiotensin system (RAS) is a significant goal for hemodynamic and metabolism-related deformities in DN. However, the pathogenesis of DN is multifactorial so novel approaches other than glucose and blood pressure control are required for treatment. This review briefly summarizes the reported pathogenesis of DN, current interventions for its treatment, and possible novel interventions to unweave the thread of DN.
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22
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Zhang Q, Yang M, Xiao Y, Han Y, Yang S, Sun L. Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy. Curr Med Chem 2021; 28:1003-1024. [PMID: 31701843 DOI: 10.2174/0929867326666191108160643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function, which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic, and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension, and dyslipidaemia is not enough to slow the progression of DN. Recent studies emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.
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Affiliation(s)
- Qin Zhang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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23
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Endothelin-targeted new treatments for proteinuric and inflammatory glomerular diseases: focus on the added value to anti-renin-angiotensin system inhibition. Pediatr Nephrol 2021; 36:763-775. [PMID: 32185491 DOI: 10.1007/s00467-020-04518-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/06/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022]
Abstract
Chronic kidney disease (CKD) is the main cause of end-stage renal disease worldwide arising as a frequent complication of diabetes, obesity, and hypertension. Current therapeutic options, mainly based of inhibition of the renin-angiotensin system (RAS), provide imperfect renoprotection if started at an advanced phase of the disease, and treatments that show or even reverse the progression of CKD are needed. The endothelin (ET) system contributes to the normal renal physiology; however, robust evidence suggests a key role of ET-1 and its cognate receptors, in the progression of CKD. The effectiveness of ET receptor antagonists in ameliorating renal hemodynamics and fibrosis has been largely demonstrated in different experimental models. A significant antiproteinuric effect of ET receptor antagonists has been found in diabetic and non-diabetic CKD patients even on top of RAS blockade, and emerging evidence from ongoing clinical trials highlights their beneficial effects on a wide range of kidney disorders.
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24
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Xie H, Wang H, Wu Q, Peng J, Huang H, Wang Y, Huang M, Jiang W, Yang Y, Zhang X, Zhang J, Zhu Q. Endothelin-1/Endothelin Receptor Type A-Angiopoietins/Tie-2 Pathway in Regulating the Cross Talk Between Glomerular Endothelial Cells and Podocytes in Trichloroethylene-Induced Renal Immune Injury. J Inflamm Res 2021; 14:761-776. [PMID: 33727850 PMCID: PMC7955787 DOI: 10.2147/jir.s301104] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Introduction This study aimed to investigate the mechanism in regulating the cross talk between glomerular endothelial cells and podocytes in “occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT)” patients. Methods Totally 6 OMLDT patients, 18 controls, and 102 BALB/c female mice were involved in this study. Patient’s serum endothelin-1 (ET-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), blood urea nitrogen (BUN), and podocalyxin (PCX) were detected. All the mice were used to establish the trichloroethylene (TCE) sensitized mouse model. Transmission electron microscope results were used to reflect renal glomerulus injury. Protein levels were detected by Western blot. Ang-1/Ang-2 gene level was reflected by RT-PCR. Cell apoptosis level was detected by using TUNEL assay kit. Results We found that in OMLDT patients, ET-1, Ang-2, BUN, and PCX were highly expressed but Ang-1 was inhibited. In TCE sensitized positive mouse, the downregulation of Ang-1, pTie-2 and the upregulation of Ang-2 were mediated by ET-1/ETAR but not ET-1/ETBR. The promotor of apoptosis proteins was downregulated and the inhibitor of apoptosis proteins was upregulated by treating with BQ123. Discussion ET-1/ETAR-Angs/Tie-2 pathway mediated the cross talk between glomerular endothelial cells and podocytes. BQ123 can alleviate glomerulus immune injury.
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Affiliation(s)
- Haibo Xie
- Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, People's Republic of China
| | - Hui Wang
- Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, People's Republic of China
| | - Qifeng Wu
- Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong Province, People's Republic of China
| | - Jiale Peng
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Hua Huang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Yican Wang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Meng Huang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Wei Jiang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Yi Yang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Xuesong Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Jiaxiang Zhang
- Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, People's Republic of China.,Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Qixing Zhu
- Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, People's Republic of China
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Greater high-mobility group box 1 in male compared with female spontaneously hypertensive rats worsens renal ischemia-reperfusion injury. Clin Sci (Lond) 2021; 134:1751-1762. [PMID: 32608481 DOI: 10.1042/cs20200575] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/26/2020] [Accepted: 07/01/2020] [Indexed: 12/29/2022]
Abstract
Renal ischemia is the most common cause of acute kidney injury. Damage-associated molecular patterns (DAMPs) initiate an inflammatory response and contribute to ischemia-reperfusion (IR) injury in males, yet the contribution of DAMPs to IR injury in females is unknown. The goal of the current study was to test the hypothesis that males have greater increases in the DAMP high-mobility group box 1 (HMGB1), worsening injury compared with females. Thirteen-week-old male and female spontaneously hypertensive rats (SHR) were subjected to sham or 45-min warm bilateral ischemia followed by 24 h of reperfusion before measurement of HMGB1 and renal function. Additional SHR were pre-treated with control (IgG) or HMGB1 neutralizing antibody (300 µg/rat) 1 h prior to renal ischemia. Blood, urine and kidneys were harvested 24 h post-IR for histological and Western blot analyses. Initial studies confirmed that IR resulted in greater increases in renal HMGB1 in male SHR compared with females. Greater renal HMGB1 in male SHR post-IR resulted in greater increases in serum TNF-α and renal IL-1β, neutrophil infiltration and tubular cell death. Neutralization of HMGB1 attenuated IR-induced increases in plasma creatinine, blood urea nitrogen (BUN), inflammation, tubular damage and tubular cell death only in male SHR. In conclusion, our data demonstrate that there is a sex difference in the contribution of HMGB1 to IR-induced injury, where males exhibit greater increases in HMGB1-mediated renal injury in response to IR compared with females.
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Sembach FE, Østergaard MV, Vrang N, Feldt-Rasmussen B, Fosgerau K, Jelsing J, Fink LN. Rodent models of diabetic kidney disease: human translatability and preclinical validity. Drug Discov Today 2021; 26:200-217. [DOI: 10.1016/j.drudis.2020.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/27/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023]
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Zhou Y, Chi J, Huang Y, Dong B, Lv W, Wang YG. Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta-analysis of randomized controlled trials. Diabet Med 2021; 38:e14411. [PMID: 33000477 DOI: 10.1111/dme.14411] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/10/2020] [Accepted: 09/22/2020] [Indexed: 01/01/2023]
Abstract
AIM To analyse the efficacy and safety of endothelin receptor antagonists for people with diabetic kidney disease. METHODS Randomized controlled trials comparing endothelin receptor antagonists with placebo in people with diabetic kidney disease were identified through PubMed, Embase and the Cochrane Library. We used a random-effect model to calculate the mean difference or risk ratio with the 95% CI. RESULTS Seven studies with a total of 4730 participants were included. Overall, endothelin receptor antagonists significantly reduced albuminuria compared with placebo (standardized mean difference -0.48, 95% CI -0.64 to -0.33). Atrasentan, in particular, effectively reduced albuminuria (standardized mean difference -0.58, 95% CI -1.00 to -0.17) and the risk of composite renal endpoints (risk ratio 0.65; 95% CI 0.49 to 0.88), with insignificant change in the rate of congestive heart failure (risk ratio 1.40, 95% CI 0.76 to 2.56) and mortality (risk ratio 1.11, 95% CI 0.77 to 1.61). In contrast, although avosentan reduced albuminuria (standardized mean difference -0.47, 95% CI -0.57 to -0.36) and the risk of composite renal endpoints (risk ratio 0.63, 95% CI 0.42 to 0.94), it was associated with a significant increase in congestive heart failure risk (risk ratio 2.61, 95% CI 1.36 to 5.00) and an insignificant increase in mortality risk (risk ratio 1.50, 95% CI 0.81, 2.78). No significant change in efficacy or safety outcomes with bosentan was detected. Dose-response analysis indicated that 0.75 mg/day atrasentan is expected to be optimal for renoprotection, with maximal albuminuria reduction and minimal fluid retention events. CONCLUSIONS Among the endothelin receptor antagonists, atrasentan and avosentan, but not bosentan, are effective for renoprotection in people with diabetic kidney disease. Compared with other types and doses, atrasentan 0.75 mg/day is the most promising, with maximal albuminuria reduction and minimal fluid retention. Vigilant monitoring of congestive heart failure risk is needed in future clinical practice. (PROSPERO registration no. CRD42020169840).
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Affiliation(s)
- Y Zhou
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - J Chi
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - Y Huang
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - B Dong
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - W Lv
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - Y G Wang
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
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Provenzano M, Andreucci M, Garofalo C, Minutolo R, Serra R, De Nicola L. Selective endothelin A receptor antagonism in patients with proteinuric chronic kidney disease. Expert Opin Investig Drugs 2020; 30:253-262. [PMID: 33356648 DOI: 10.1080/13543784.2021.1869720] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Selective antagonists of Endothelin-1 receptors (ERA) have been tested in diabetic and nondiabetic chronic kidney disease (CKD). The SONAR trial (Study Of diabetic Nephropathy with AtRasentan) was the first randomized, phase 3, study assessing the long-term effect of ERA on CKD progression.Areas covered: We examine the ERA effects in proteinuric CKD. We discuss the results of the main clinical studies on ERA in CKD and offer an opinion on the findings of SONAR study and future perspectives in this field. We searched in PubMed and ISI Web of Science databases for including experimental and clinical studies that evaluated ERA in proteinuric CKD.Expert opinion: The SONAR study demonstrated that ERA confers protection against risk for CKD progression. This trial stimulated clinical research on ERA, to expand the therapeutic opportunities in CKD patients. Two novel phase 3 studies testing ERA in patients with glomerular disease are ongoing. Within the context of personalized medicine, we think it would be relevant to evaluate the effect of multiple treatments, including ERA, in proteinuric CKD patients. Testing ERA in clinical trials of novel design will also help at identifying the patients who would more benefit from these drugs.
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Affiliation(s)
- Michele Provenzano
- Renal Unit, Department of Health Sciences, "Magna Grecia" University, Catanzaro, Italy
| | - Michele Andreucci
- Renal Unit, Department of Health Sciences, "Magna Grecia" University, Catanzaro, Italy
| | - Carlo Garofalo
- Nephrology Division, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Roberto Minutolo
- Nephrology Division, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Raffaele Serra
- Interuniversity Center of Phlebolymphology (CIFL), "Magna Graecia" University of Catanzaro, Catanzaro, Italy.,Department of Medical and Surgical Sciences, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Luca De Nicola
- Nephrology Division, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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Zhang L, Xue S, Hou J, Chen G, Xu ZG. Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review. World J Diabetes 2020; 11:553-566. [PMID: 33269066 PMCID: PMC7672789 DOI: 10.4239/wjd.v11.i11.553] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/22/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented. AIM To assess the effectiveness and safety of ER antagonists among patients with DN. METHODS The EMBASE, PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched without any language restrictions. Relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software. Publication bias was assessed using Egger's test with Stata/SE software. RESULTS We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic and diastolic blood pressure were observed in the invention group. CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor /angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Xue
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guang Chen
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zhong-Gao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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30
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Pirklbauer M, Bernd M, Fuchs L, Staudinger P, Corazza U, Leierer J, Mayer G, Schramek H. Empagliflozin Inhibits Basal and IL-1β-Mediated MCP-1/CCL2 and Endothelin-1 Expression in Human Proximal Tubular Cells. Int J Mol Sci 2020; 21:ijms21218189. [PMID: 33139635 PMCID: PMC7663377 DOI: 10.3390/ijms21218189] [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: 10/06/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/21/2022] Open
Abstract
SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1β as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1β (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (n = 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1β upregulated basal MCP-1/CCL2 (15- and 19-fold) and ET-1 (3- and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6- and 0.5-fold) and ET-1 (0.3- and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1β-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1β-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection.
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Czopek A, Moorhouse R, Guyonnet L, Farrah T, Lenoir O, Owen E, van Bragt J, Costello HM, Menolascina F, Baudrie V, Webb DJ, Kluth DC, Bailey MA, Tharaux PL, Dhaun N. A novel role for myeloid endothelin-B receptors in hypertension. Eur Heart J 2020; 40:768-784. [PMID: 30657897 PMCID: PMC6396028 DOI: 10.1093/eurheartj/ehy881] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 09/04/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022] Open
Abstract
AIMS Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype. METHODS AND RESULTS In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. CONCLUSION Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
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Affiliation(s)
- Alicja Czopek
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Rebecca Moorhouse
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Léa Guyonnet
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Tariq Farrah
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Olivia Lenoir
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Elizabeth Owen
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Job van Bragt
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Hannah M Costello
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Filippo Menolascina
- School of Engineering & SynthSys, Institute for Bioengineering, Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, UK.,MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Véronique Baudrie
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - David J Webb
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - David C Kluth
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Matthew A Bailey
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
| | - Pierre-Louis Tharaux
- Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.,Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Neeraj Dhaun
- BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.,Paris Cardiovascular Research Centre - PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
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Arfian N, Suzuki Y, Hartopo AB, Anggorowati N, Nugrahaningsih DAA, Emoto N. Endothelin converting enzyme-1 (ECE-1) deletion in association with Endothelin-1 downregulation ameliorates kidney fibrosis in mice. Life Sci 2020; 258:118223. [PMID: 32768584 DOI: 10.1016/j.lfs.2020.118223] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 01/16/2023]
Abstract
Kidney fibrosis is a common final pathway of chronic kidney diseases, which are characterized by renal architecture damage, inflammation, fibroblast expansion and myofibroblast formation. Endothelin converting enzyme-1 (ECE-1) contributes to activation of Endothelin-1 (ET-1), a potent vasoconstrictor and pro-fibrotic substance. This study elucidated the effect of ECE-1 knockout in kidney fibrosis model in mice in association of ET-1 downregulation. Kidney fibrosis was performed in ECE-1 knockout (ECE-1 KO) and vascular endothelial derived ET-1 KO (VEETKO) mice (2 months, 20-30 g, n = 30) and their wild type (WT) littermates using unilateral ureteral obstruction (UUO) procedure. Mice were euthanized on day-7 and day-14 after UUO. Histopathological analysis was conducted for fibrosis and tubular injury. Immunostainings were done to quantify macrophages (F4/80), fibroblasts (FSP-1) and myofibroblasts (α-SMA). Monocyte Chemoattractant Protein-1 (MCP-1), ECE-1 and preproET-1 (ppET-1) mRNA expression were quantified with qRT-PCR, while Transforming Growth Factor-β1 (TGF-β1) and α-SMA protein level were quantified with Western blot. ECE-1 KO mice demonstrated reduction of ECE-1 and ppET-1 mRNA expression, attenuation of kidney fibrosis, tubular injury, MCP-1 mRNA expression and macrophage number compared to WT. Double immunostaining revealed fibroblast to myofibroblast formation after UUO, while ECE-1 KO mice had significantly lower fibroblast number and myofibroblast formation compared to WT, which were associated with significantly lower TGF-β1 and α-SMA protein levels in day-14 of UUO. VEETKO mice also demonstrated attenuation of ET-1 protein level, fibrosis and myofibroblast formation. In conclusion, ECE-1 knockout and ET-1 downregulation attenuated kidney fibrosis.
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Affiliation(s)
- Nur Arfian
- Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Yoko Suzuki
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe, Japan.
| | - Anggoro Budi Hartopo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Nungki Anggorowati
- Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Dwi Aris Agung Nugrahaningsih
- Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
| | - Noriaki Emoto
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
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The endothelin system as target for therapeutic interventions in cardiovascular and renal disease. Clin Chim Acta 2020; 506:92-106. [DOI: 10.1016/j.cca.2020.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 12/12/2022]
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Deletion of the myeloid endothelin-B receptor confers long-term protection from angiotensin II-mediated kidney, eye and vessel injury. Kidney Int 2020; 98:1193-1209. [PMID: 32569653 PMCID: PMC7652550 DOI: 10.1016/j.kint.2020.05.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/25/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022]
Abstract
The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ETB) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ETB signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ETB receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages.
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Ishimwe JA, Garrett MR, Sasser JM. 1,3-Butanediol attenuates hypertension and suppresses kidney injury in female rats. Am J Physiol Renal Physiol 2020; 319:F106-F114. [PMID: 32508113 DOI: 10.1152/ajprenal.00141.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Thirty-seven million people in the United States are estimated to have chronic kidney disease (CKD). Hypertension (HTN) is the second leading risk factor for developing kidney disease. A recent study reported that increasing levels of β-hydroxybutyrate levels by administration of its precursor, 1,3-butanediol, decreased salt-induced HTN in male Dahl salt-sensitive (S) rats. The effect of 1,3-butanediol on hypertensive kidney disease in female rats or the absence of high salt has not been investigated. This study tested the hypothesis that 1,3-butanediol attenuates HTN and the progression of CKD in female S-SHR(11) rats. The S-SHR(11) strain is a congenic rat strain generated from genetic modification of the Dahl S rat, previously characterized as a model of accelerated renal disease. Rats received 1,3-butanediol (20% via drinking water) or control for 10 wk and were maintained on a 0.3% NaCl rodent diet (n = 12-14 rats/group). Blood pressure was measured after 6 and 9 wk of treatment by tail-cuff plethysmography; after 10 wk, urine and tissues were collected. Activity of the treatment was confirmed by measuring plasma β-hydroxybutyrate levels, which were greater in the treated group. The 1,3-butanediol-treated group had lower systolic blood pressure, proteinuria, plasma creatinine, and renal fibrosis after 9 wk of treatment compared with controls. The treated group had significantly smaller spleens and increased the renal anti-inflammatory molecules interleukin-10 and granulocyte-macrophage colony-stimulating factor, suggesting reduced inflammation. The present data demonstrate that 1,3-butanediol lowers blood pressure and renal injury in female rats and could be a novel nutritional intervention for the treatment of CKD.
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Affiliation(s)
- Jeanne A Ishimwe
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Michael R Garrett
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Jennifer M Sasser
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
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Barrera-Chimal J, Jaisser F. Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets. Diabetes Obes Metab 2020; 22 Suppl 1:16-31. [PMID: 32267077 DOI: 10.1111/dom.13969] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/07/2020] [Accepted: 01/13/2020] [Indexed: 12/22/2022]
Abstract
Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease around the globe and is one of the main complications in patients with type 1 and 2 diabetes. The standard treatment for DKD is drugs controlling hyperglycemia and high blood pressure. Renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition have yielded promising results in DKD, but many diabetic patients on such treatments nevertheless continue to develop DKD, leading to kidney failure and cardiovascular comorbidities. New therapeutic options are urgently required. We review here the promising therapeutic avenues based on insights into the mechanisms of DKD that have recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonist, endothelin receptor A inhibition, anti-inflammatory agents, autophagy activators and epigenetic remodelling. The involvement of several molecular mechanisms in DKD pathogenesis, together with the genetic and epigenetic variability of this condition, makes it difficult to target this heterogeneous patient population with a single drug. Personalized medicine, taking into account the genetic and mechanistic variability, may therefore improve renal and cardiovascular protection in diabetic patients with DKD.
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Affiliation(s)
- Jonatan Barrera-Chimal
- Laboratorio de Fisiología Cardiovascular y Trasplante Renal, Unidad de Investigación en Medicina Traslacional, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Frédéric Jaisser
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
- INSERM U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France
- INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Nancy, France
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Patel DM, Bose M, Cooper ME. Glucose and Blood Pressure-Dependent Pathways-The Progression of Diabetic Kidney Disease. Int J Mol Sci 2020; 21:ijms21062218. [PMID: 32210089 PMCID: PMC7139394 DOI: 10.3390/ijms21062218] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/17/2020] [Accepted: 03/17/2020] [Indexed: 12/11/2022] Open
Abstract
The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.
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Affiliation(s)
- Devang M. Patel
- Department of Diabetes, Monash University Central, Clinical School, Melbourne, VIC 3004, Australia;
- Correspondence: (D.M.P.); (M.E.C.)
| | - Madhura Bose
- Department of Diabetes, Monash University Central, Clinical School, Melbourne, VIC 3004, Australia;
| | - Mark E. Cooper
- Department of Diabetes, Monash University Central, Clinical School, Melbourne, VIC 3004, Australia;
- Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, VIC 3004, Australia
- Correspondence: (D.M.P.); (M.E.C.)
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38
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Aragón CC, Tafúr RA, Suárez-Avellaneda A, Martínez MDT, Salas ADL, Tobón GJ. Urinary biomarkers in lupus nephritis. J Transl Autoimmun 2020; 3:100042. [PMID: 32743523 PMCID: PMC7388339 DOI: 10.1016/j.jtauto.2020.100042] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 01/07/2020] [Accepted: 02/06/2020] [Indexed: 02/08/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease that can affect any organ of the body. Multiple mechanisms may contribute to the pathophysiology of systemic lupus, including failure to remove apoptotic bodies, hyperactivity of self-reactive B and T lymphocytes, abnormal exposure to autoantigens, and increased levels of B-cell stimulatory cytokines. The involvement of the kidney, called lupus nephritis (LN), during the course of the disease affects between 30% and 60% of adult SLE patients, and up to 70% of children. LN is an immune-mediated glomerulonephritis that is a common and serious finding in patients with SLE. Nowadays, renal biopsy is considered the gold standard for classifying LN, besides its degree of activity or chronicity. Nevertheless, renal biopsy lacks the ability to predict which patients will respond to immunosuppressive therapy and is a costly and risky procedure that is not practical in the monitoring of LN because serial repetitions would be necessary. Consequently, many serum and urinary biomarkers have been studied in SLE patients for the complementary study of LN, existing conventional biomarkers like proteinuria, protein/creatinine ratio in spot urine, 24 h urine proteinuria, creatinine clearance, among others and non-conventional biomarkers, like Monocyte chemoattractant protein-1 (MCP-1), have been correlated with the histological findings of the different types of LN. In this article, we review the advances in lupus nephritis urinary biomarkers. Such markers ideally should be capable of predicting early sub-clinical flares and could be used to follow response to therapy. In addition, some of these markers have been found to be involved in the pathogenesis of lupus nephritis.
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Affiliation(s)
- Cristian C. Aragón
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
| | - Raúl-Alejandro Tafúr
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Ana Suárez-Avellaneda
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
| | - MD. Tatiana Martínez
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Alejandra de las Salas
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Gabriel J. Tobón
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
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Abstract
Discovered in 1987 as a potent endothelial cell-derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics-the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ETA autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ETB agonists, novel biologics such as receptor-targeting antibodies, or immunization against ETA receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.
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Affiliation(s)
- Matthias Barton
- From Molecular Internal Medicine, University of Zürich, Switzerland (M.B.)
- Andreas Grüntzig Foundation, Zürich, Switzerland (M.B.)
| | - Masashi Yanagisawa
- International Institute for Integrative Sleep Medicine (WPI-IIIS) and Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan (M.Y.)
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX (M.Y.)
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Abdel Moneim LM, Helmy MW, El-Abhar HS. Co-targeting of endothelin- A and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity. Pharmacol Rep 2019; 71:917-925. [PMID: 31430707 DOI: 10.1016/j.pharep.2019.04.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 04/08/2019] [Accepted: 04/24/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Although modulation of the vitamin D receptor (VDR) and endothelin-A receptor (ETAR) has previously been reported to offer renoprotection against cisplatin-induced nephrotoxicity, the possible interaction between the ET-1 and vitamin D pathways remains obscure. Therefore, the present study addressed the possible interaction between these signalling pathways using BQ-123 (a selective ETAR blocker) and alfacalcidol (a vitamin D3 analogue) separately or in combination. METHODS Male Sprague-Dawley rats were divided into the following groups: control (DMSO orally), cisplatin (single dose of 6 mg/kg ip; nephrotoxicity model), cisplatin + BQ-123 (1 mg/kg BQ-123 ip 1 h before and 1 day after cisplatin), cisplatin + alfacalcidol (50 ng/kg alfacalcidol orally 5 days before and 14 days after cisplatin), and cisplatin + BQ-123+alfacalcidol. Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration. RESULTS Both BQ-123 and alfacalcidol counteracted cisplatin-induced nephrotoxic changes. Specifically, they reduced serum creatinine and urea levels; renal tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), and phosphorylated nuclear factor-kappa B (pNF-κB) content; and caspase-3 activity. They downregulated ET-1 and ETAR expression and ameliorated cisplatin-induced acute tubular necrosis. In addition, the treatments have increased VDR and endothelin-B receptor (ETBR) expression; however, BQ-123 did not affect ETBR. The effect of the combination regimen surpassed that of each drug alone. CONCLUSION These findings highlight the potential cross-talk between vitamin D and ET-1 pathways and pave the way for future preclinical/clinical studies to explore further mechanisms involved in this cross-talk.
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Affiliation(s)
- Lobna M Abdel Moneim
- Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Maged W Helmy
- Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, El-Bahira, Egypt.
| | - Hanan S El-Abhar
- Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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41
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Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray JJV, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 2019; 393:1937-1947. [PMID: 30995972 DOI: 10.1016/s0140-6736(19)30772-x] [Citation(s) in RCA: 441] [Impact Index Per Article: 73.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/14/2019] [Accepted: 03/20/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. METHODS We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. FINDINGS Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65). INTERPRETATION Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. FUNDING AbbVie.
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Affiliation(s)
- Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
| | - Hans-Henrik Parving
- Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Science, Aarhus University, Aarhus, Denmark
| | | | - George Bakris
- American Society of Hypertension Comprehensive Hypertension Center, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA
| | - Ricardo Correa-Rotter
- National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico
| | - Fan-Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China
| | | | - Donald Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | | | - John J V McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Joel Z Melnick
- Pharmaceutical Development, AbbVie, North Chicago, IL, USA
| | | | | | - Vlado Perkovic
- George Institute for Global Health and University of New South Wales, Sydney, NSW, Australia
| | - Sheldon Tobe
- Division of Nephrology, Sunnybrook Health Sciences Centre, University of Toronto and the Northern Ontario School of Medicine, Toronto, ON, Canada
| | - Tingting Yi
- Pharmaceutical Development, AbbVie, North Chicago, IL, USA
| | | | - Dick de Zeeuw
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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De Miguel C, Sedaka R, Kasztan M, Lever JM, Sonnenberger M, Abad A, Jin C, Carmines PK, Pollock DM, Pollock JS. Tauroursodeoxycholic acid (TUDCA) abolishes chronic high salt-induced renal injury and inflammation. Acta Physiol (Oxf) 2019; 226:e13227. [PMID: 30501003 DOI: 10.1111/apha.13227] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 10/23/2018] [Accepted: 11/22/2018] [Indexed: 12/23/2022]
Abstract
AIM Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional ETB receptors. Tauroursodeoxycholic acid (TUDCA) is a chemical chaperone and bile salt that is approved for the treatment of hepatic diseases. Our aim was to determine whether TUDCA is reno-protective in a model of ETB receptor deficiency with chronic high salt-induced renal injury and inflammation. METHODS ETB -deficient and transgenic control rats were placed on normal (0.8% NaCl) or high salt (8% NaCl) diet for 3 weeks, receiving TUDCA (400 mg/kg/d; ip) or vehicle. Histological and biochemical markers of kidney injury, renal cell death and renal inflammation were assessed. RESULTS In ETB -deficient rats, high salt diet significantly increased glomerular and proximal tubular histological injury, proteinuria, albuminuria, excretion of tubular injury markers KIM-1 and NGAL, renal cortical cell death and renal CD4+ T cell numbers. TUDCA treatment increased proximal tubule megalin expression as well as prevented high salt diet-induced glomerular and tubular damage in ETB -deficient rats, as indicated by reduced kidney injury markers, decreased glomerular permeability and proximal tubule brush border restoration, as well as reduced renal inflammation. However, TUDCA had no significant effect on blood pressure. CONCLUSIONS TUDCA protects against the development of glomerular and proximal tubular damage, decreases renal cell death and inflammation in the renal cortex in rats with ETB receptor dysfunction on a chronic high salt diet. These results highlight the potential use of TUDCA as a preventive tool against chronic high salt induced renal damage.
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Affiliation(s)
- Carmen De Miguel
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Randee Sedaka
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Malgorzata Kasztan
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Jeremie M. Lever
- Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Michelle Sonnenberger
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Andrew Abad
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Chunhua Jin
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Pamela K. Carmines
- Department of Cellular and Integrative Physiology University of Nebraska Medical Center Omaha Nebraska
| | - David M. Pollock
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
| | - Jennifer S. Pollock
- Section of Cardio‐Renal Physiology and Medicine, Division of Nephrology, Department of Medicine University of Alabama at Birmingham Birmingham Alabama
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Yuan M, Tan Y, Wang Y, Wang SX, Yu F, Zhao MH. The associations of endothelial and podocyte injury in proliferative lupus nephritis: from observational analysis to in vitro study. Lupus 2019; 28:347-358. [PMID: 30755145 DOI: 10.1177/0961203319828509] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our study aims to evaluate the endothelial cell-podocyte crosstalk in proliferative lupus nephritis (LN). The semi-quantification scores of glomerular endothelial cell injury and the foot process width (FPW) were processed in 110 proliferative LN patients. Podocytes were stimulated with LN-derived IgG. Glomerular endothelial cells were treated with podocyte-conditioned medium (PCM), and then podocytes were incubated with endothelial cell-conditioned medium (ECM). The levels of vascular endothelial growth factor-A (VEGF-A) in PCM and endothelin-1 in ECM were analyzed, and the injury of podocyte and glomerular endothelial cells were further evaluated. The pathological score of glomerular endothelial cell injury was correlated with FPW in LN complicated with thrombotic microangiopathy. In vitro study showed the following: 1. Stimulation of podocytes by IgG from LN led to decline in the expression of nephrin with cytoskeleton rearrangement, and reduction of VEGF-A levels. 2. Exposure of glomerular endothelial cells to PCM incubated with LN-derived IgG (PCM-LN) induced more endothelin-1 secretion and disruption of intercellular tight junction. 3. Exposure of podocytes to ECM stimulated with PCM-LN could induce cytoskeleton redistribution with decrease of nephrin. In conclusion, the pathological glomerular endothelial cell lesions were associated with FPW and the VEGF-endothelin-1 system might play a critical role in the endothelial cell-podocyte crosstalk in LN.
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Affiliation(s)
- M Yuan
- 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,2 Institute of Nephrology, Peking University, Beijing, People's Republic of China.,3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China
| | - Y Tan
- 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,2 Institute of Nephrology, Peking University, Beijing, People's Republic of China.,3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China
| | - Y Wang
- 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,2 Institute of Nephrology, Peking University, Beijing, People's Republic of China.,3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China
| | - S X Wang
- 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,2 Institute of Nephrology, Peking University, Beijing, People's Republic of China.,3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China
| | - F Yu
- 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,2 Institute of Nephrology, Peking University, Beijing, People's Republic of China.,3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China.,5 Department of Nephrology, Peking University International Hospital, Beijing, People's Republic of China
| | - M H Zhao
- 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,2 Institute of Nephrology, Peking University, Beijing, People's Republic of China.,3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China.,6 Peking-Tsinghua Center for Life Sciences, Beijing, People's Republic of China
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Tung CW, Hsu YC, Shih YH, Chang PJ, Lin CL. Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton) 2019; 23 Suppl 4:32-37. [PMID: 30298646 DOI: 10.1111/nep.13451] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Diabetic nephropathy is one of the leading causes of end-stage renal disease and creates heavy healthcare burdens globally. Dysfunction of mesangial cells and podocytes contributes to diabetic nephropathy. Dysregulation of signaling involved in renal development and regeneration may cause diabetic kidney damages. Growing evidences suggest the importance of dysregulated dickkopf-1 (DKK1)/Wnt/ β-catenin signaling pathways in the pathogenesis of diabetic glomerular injuries. The inhibition of Wnt signaling in injured mesangial cells is likely attributed to the high glucose-induced Ras/Rac1 dependent superoxide formation. When DKK1, the cellular inhibitor of Wnt signaling, binds to the Kremen-2 receptor, depositions of extracellular matrix increase in the mesangium of diabetic kidneys. Additionally, reactivation of Notch-1 signaling has been implicated in podocytopathy during diabetic proteinuria development. Knocking down Notch-1 alleviates vascular endothelial growth factor (VEGF) expression, nephrin repression and proteinuria in diabetic kidneys. It is also found that epigenetic modulations by histone deacetylase 4 (HDAC4) and miR-29a could lead to diabetic nephropathy. High glucose increases the expression of HDAC4, which causes deacetylation with subsequent ubiquitination of nephrin. Overexpression of miR-29a in diabetic transgenic mice would decrease the expression of HDAC4 and stabilize nephrin. Surprisingly, reprogramming or reactivation of signaling involved in renal development or regeneration often brings about diabetic glomerular sclerosis in mesangial cells and podocytes. Better knowledge about modifications of embryonic stem cell signaling will have a chance to implement strategically focused pharmacological research programs aiming to the development of new drugs for diabetic kidney injuries.
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Affiliation(s)
- Chun-Wu Tung
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ya-Hsueh Shih
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Pey-Jium Chang
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City, Taiwan
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.,Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan.,College of Medicine, Chang Gung University, Taoyuan City, Taiwan.,Kidney Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Department of Medical Research, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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45
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Kang KT, Sullivan JC, Pollock JS. Superoxide Dismutase Activity in Small Mesenteric Arteries Is Downregulated by Angiotensin II but Not by Hypertension. Toxicol Res 2018; 34:363-370. [PMID: 30370011 PMCID: PMC6195877 DOI: 10.5487/tr.2018.34.4.363] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 01/14/2023] Open
Abstract
Many studies reported reduced antioxidant capacity in the vasculature under hypertensive conditions. However, little is known about the effects of antihypertensive treatments on the regulation of vascular antioxidant enzymes. Thus, we hypothesized that antihypertensive treatments prevent the reduction of antioxidant enzyme activity and expression in the small vessels of angiotensin II-induced hypertensive rats (ANG). We observed the small mesenteric arteries and small renal vessels of normotensive rats (NORM), ANG, and ANG treated with a triple antihypertensive therapy of reserpine, hydrochlorothiazide, and hydralazine (ANG + TTx). Systolic blood pressure was increased in ANG, which was attenuated by 2 weeks of triple therapy (127, 191, and 143 mmHg for NORM, ANG, and ANG + TTx, respectively; p < 0.05). Total superoxide dismutase (SOD) activity in the small mesenteric arteries of ANG was lower than that of NORM. The protein expression of SOD1 was lower in ANG than in NORM, whereas SOD2 and SOD3 expression was not different between the groups. Reduced SOD activity and SOD1 expression in ANG was not restored in ANG + TTx. Both SOD activity and SOD isoform expression in the small renal vessels of ANG were not different from those of NORM. Interestingly, SOD activity in the small renal vessels was reduced by TTx. Between groups, there was no difference in catalase activity or expression in both the small mesenteric arteries and small renal vessels. In conclusion, SOD activity in the small mesenteric arteries decreased by angiotensin II administration, but not by hypertension, which is caused by decreased SOD1 expression.
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Affiliation(s)
- Kyu-Tae Kang
- College of Pharmacy, Duksung Innovative Drug Center, Duksung Women's University, Seoul, Korea
| | - Jennifer C Sullivan
- Department of Physiology, Augusta University, Augusta, GA, USA.,Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Jennifer S Pollock
- Medical College of Georgia, Augusta University, Augusta, GA, USA.,Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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46
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Boesen EI. ET A receptor activation contributes to T cell accumulation in the kidney following ischemia-reperfusion injury. Physiol Rep 2018; 6:e13865. [PMID: 30198212 PMCID: PMC6129774 DOI: 10.14814/phy2.13865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 08/20/2018] [Indexed: 12/19/2022] Open
Abstract
Renal ischemia-reperfusion (IR) injury and acute kidney injury (AKI) increase the risk of developing hypertension, with T cells suspected as a possible mechanistic link. Endothelin promotes renal T cell infiltration in several diseases, predominantly via the ETA receptor, but its contribution to renal T cell infiltration following renal IR injury is poorly understood. To test whether ETA receptor activation promotes T cell infiltration of the kidney following IR injury, male C57BL/6 mice were treated with the ETA receptor antagonist ABT-627 or vehicle, commencing 2 days prior to unilateral renal IR injury. Mice were sacrificed at 24 h or 10 days post-IR for assessment of the initial renal injury and subsequent infiltration of T cells. Vehicle and ABT-627-treated mice displayed significant upregulation of endothelin-1 (ET-1) in the IR compared to contralateral kidney at both 24 h and 10 days post-IR (P < 0.001). Renal CD3+ T cell numbers were increased in the IR compared to contralateral kidneys at 10 days, but ABT-627-treated mice displayed a 35% reduction in this effect in the outer medulla (P < 0.05 vs. vehicle) and a nonsignificant 23% reduction in the cortex compared to vehicle-treated mice. Whether specific T cell subsets were affected awaits confirmation by flow cytometry, but outer medullary expression of the T helper 17 transcription factor RORγt was reduced by ABT-627 (P = 0.06). These data indicate that ET-1 acting via the ETA receptor contributes to renal T cell infiltration post-IR injury. This may have important implications for immune system-mediated long-term consequences of AKI, an area which awaits further investigation.
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Affiliation(s)
- Erika I. Boesen
- Department of Cellular and Integrative PhysiologyUniversity of Nebraska Medical CenterOmahaNebraska
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47
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Heerspink HJL, Andress DL, Bakris G, Brennan JJ, Correa‐Rotter R, Dey J, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray J, Perkovic V, Tobe S, Wigderson M, Parving H, de Zeeuw D. Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy. Diabetes Obes Metab 2018; 20:1369-1376. [PMID: 29405626 PMCID: PMC5969254 DOI: 10.1111/dom.13245] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 01/30/2018] [Accepted: 02/01/2018] [Indexed: 02/06/2023]
Abstract
AIMS Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. MATERIALS AND METHODS SONAR is a randomized, double-blind, placebo-controlled trial with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor. RESULTS After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). CONCLUSION SONAR aims to determine whether atrasentan added to guideline-recommended therapies safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial "surrogate" response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.
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Affiliation(s)
- Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | | | - George Bakris
- Department of Medicine, Section of Endocrinology, ASH Comprehensive Hypertension CenterUniversity of Chicago Medicine and Biological SciencesChicagoIllinois
| | | | - Ricardo Correa‐Rotter
- Department of Nephrology and Mineral Metabolism, National Medical Science and Nutrition Institute Salvador ZubiránMexico CityMexico
| | | | - Fan Fan Hou
- Division of NephrologyNanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney DiseaseGuangzhouChina
| | - Dalane W. Kitzman
- Department of Internal MedicineWake Forest School of MedicineWinston‐SalemNorth Carolina
| | - Donald Kohan
- Division of NephrologyUniversity of Utah Health Sciences CenterSalt Lake CityUtah
| | - Hirofumi Makino
- Department of Nephrology, Rheumatology, Endocrinology and MetabolismOkayama UniversityOkayama‐ShiJapan
| | - John McMurray
- BHF Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
| | - Vlado Perkovic
- Faculty of MedicineGeorge Institute for Global Health, UNSW SydneyNewtownAustralia
| | - Sheldon Tobe
- Department of Medicine, Division of NephrologySunnybrook Health Sciences Centre, University of Toronto and the Northern Ontario School of MedicineTorontoCanada
| | | | - Hans‐Henrik Parving
- Department of Medical Endocrinology, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
- Faculty of Health ScienceAarhus UniversityAarhusDenmark
| | - Dick de Zeeuw
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
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48
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Spires D, Poudel B, Shields CA, Pennington A, Fizer B, Taylor L, McPherson KC, Cornelius DC, Williams JM. Prevention of the progression of renal injury in diabetic rodent models with preexisting renal disease with chronic endothelin A receptor blockade. Am J Physiol Renal Physiol 2018; 315:F977-F985. [PMID: 29846112 DOI: 10.1152/ajprenal.00182.2018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The endothelin (ET) system has emerged as a therapeutic target for the treatment of diabetic nephropathy (DN). The present study examined whether chronic endothelin A (ETA) receptor blockade with atrasentan prevents the progression of renal injury in two models of DN with preexisting renal disease that exhibit an increased renal ET-1 system compared with nondiabetic rats: streptozotocin-treated Dahl salt-sensitive (STZ-SS) and type 2 diabetic nephropathy (T2DN) rats. Nine week-old SS rats were treated with (STZ; 50 mg/kg ip) to induce diabetes. After 3 wk of diabetes, proteinuria increased to 353 ± 34 mg/day. The rats were then separated into two groups: 1) vehicle and 2) atrasentan (5 mg·kg-1·day-1) via drinking water. After 6 wk of treatment with atrasentan, mean arterial pressure (MAP) and proteinuria decreased by 12 and 40%, respectively, in STZ-SS rats. The degree of glomerulosclerosis and renal fibrosis was significantly reduced in the kidneys of atrasentan-treated STZ-SS rats compared with vehicle STZ-SS rats. Interestingly, treatment with atrasentan did not affect GFR but significantly increased renal blood flow by 33% and prevented the elevations in filtration fraction and renal vascular resistance by 23 and 20%, respectively, in STZ-SS rats. In contrast to the STZ-SS study, atrasentan had no effect on MAP or proteinuria in T2DN rats. However, treatment with atrasentan significantly decreased glomerular injury and renal fibrosis and prevented the decline in renal function in T2DN rats. These data indicate that chronic ETA blockade produces advantageous changes in renal hemodynamics that slow the progression of renal disease and also reduces renal histopathology in the absence of reducing arterial pressure and proteinuria.
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Affiliation(s)
- Denisha Spires
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Bibek Poudel
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Corbin A Shields
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Alyssa Pennington
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Brianca Fizer
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Lateia Taylor
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Kasi C McPherson
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Denise C Cornelius
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Jan M Williams
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
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49
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BISWAS S, FENG B, THOMAS A, CHEN S, AREF-ESHGHI E, SADIKOVIC B, CHAKRABARTI S. Endothelin-1 Regulation Is Entangled in a Complex Web of Epigenetic Mechanisms in Diabetes. Physiol Res 2018; 67:S115-S125. [DOI: 10.33549/physiolres.933836] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter and 5’ UTR/first exon regions of EDN1 following HG culture. Further, globally blocking DNA methylation or histone methylation significantly increased ET-1 mRNA expressions in both NG and HG-treated HRECs. While, knocking down the pathogenetic lncRNAs ANRIL, MALAT1, and ZFAS1 subsequently prevented the glucose-induced upregulation of ET-1 transcripts. Based on our past and present findings, we present a novel paradigm that reveals a complex web of epigenetic mechanisms regulating glucose-induced transcription of ET-1. Improving our understanding of such processes may lead to better targeted therapies.
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Affiliation(s)
| | | | | | | | | | | | - S. CHAKRABARTI
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
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50
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Abstract
PURPOSE OF REVIEW Despite optimal therapy of diabetic nephropathy with agents blocking the renin-angiotensin-aldosterone system, the residual risk of nephropathy progression to end-stage renal disease (ESRD) remains high. The purpose of this review is to discuss the potential role of endothelin antagonism as a therapeutic tool to reduce residual proteinuria and delay kidney injury progression among patients with diabetic nephropathy. RECENT FINDINGS Preclinical studies have shown that endothelin receptor antagonists (ERAs) exert proteinuria lowering and nephroprotective actions in experimental models of diabetic nephropathy. ERAs reduce proteinuria in phase 2 trials that included therapy with renin-angiotensin-aldosterone system blockers. Safety of these agents and protection from ESRD needs to be demonstrated in phase 3 trials. Excess risk of fluid retention and heart failure risk remains. SUMMARY The hypothesis that the antiproteinuric effect of endothelin antagonism may be translated into a slower progression of diabetic nephropathy to ESRD is investigated in ongoing randomized trials assessing 'hard' renal endpoints. ERAs may represent a promising tool toward renoprotection in diabetic nephropathy by individualizing therapy and mitigating the risk of heart failure, if these trials are positive.
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