scholarly journals The Podocyte in Diabetic Kidney Disease

2009 ◽  
Vol 9 ◽  
pp. 1127-1139 ◽  
Author(s):  
Erin Stitt-Cavanagh ◽  
Laura MacLoed ◽  
Chris R.J. Kennedy
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Peroxisome Proliferator ◽  
Diabetic Kidney ◽  
Cellular Hypertrophy ◽  
Treatment And Prevention ◽  
Filtration Barrier ◽  
Peroxisome Proliferator Activated Receptors ◽  
Stage Renal Disease

Approaching epidemic levels, diabetic kidney disease (DKD) is now the leading cause of end-stage renal disease (ESRD). Microalbuminuria is an early clinical marker of DKD that results from damage to the glomerular filtration barrier at the level of the highly differentiated glomerular podocyte cells. Injury to these epithelial cells, podocytopathies, includes cellular hypertrophy, foot process effacement, detachment from the glomerular basement membrane, and apoptosis. Here we review the role of a number of recently identified factors that contribute to podocytopathies in DKD. These factors include members of the renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) types 1 and 2, prorenin and its receptor, reactive oxygen species (ROS), prostanoids, peroxisome proliferator-activated receptors (PPAR), advanced glycation end-products (AGEs) and their receptors (RAGE), adiponectin, and microRNAs. As the number of therapeutic options that slow, but do not halt, the progression of DKD to ESRD remains limited, a more comprehensive understanding of the signaling events that contribute to this increasingly prevalent disease may identify novel avenues for treatment and prevention.

Renin-angiotensin system within the diabetic podocyte

2015 ◽  
Vol 308 (1) ◽  
pp. F1-F10 ◽  
Author(s):  
Eva Márquez ◽  
Marta Riera ◽  
Julio Pascual ◽  
María José Soler
Keyword(s):  
Angiotensin Ii ◽  
Kidney Disease ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Diabetic Kidney ◽  
Renin Angiotensin ◽  
Filtration Barrier

Diabetic kidney disease is the leading cause of end-stage renal disease. Podocytes are differentiated cells necessary for the development and maintenance of the glomerular basement membrane and the capillary tufts, as well as the function of the glomerular filtration barrier. The epithelial glomerular cells express a local renin-angiotensin system (RAS) that varies in different pathological situations such as hyperglycemia or mechanical stress. RAS components have been shown to be altered in diabetic podocytopathy, and their modulation may modify diabetic nephropathy progression. Podocytes are a direct target for angiotensin II-mediated injury by altered expression and distribution of podocyte proteins. Furthermore, angiotensin II promotes podocyte injury indirectly by inducing cellular hypertrophy, increased apoptosis, and changes in the anionic charge of the glomerular basement membrane, among other effects. RAS blockade has been shown to decrease the level of proteinuria and delay the progression of chronic kidney disease. This review summarizes the local intraglomerular RAS and its imbalance in diabetic podocytopathy. A better understanding of the intrapodocyte RAS might provide a new approach for diabetic kidney disease treatment.

scholarly journals GLP-1 Receptor Agonists and Diabetic Kidney Disease: A Call of Attention to Nephrologists

2020 ◽  
Vol 9 (4) ◽  
pp. 947 ◽  
Author(s):  
José Luis Górriz ◽  
María José Soler ◽  
Juan F. Navarro-González ◽  
Clara García-Carro ◽  
María Jesús Puchades ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Glycemic Control ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Receptor Agonists ◽  
Increased Risk ◽  
Stage Renal Disease ◽  
The Impact

Type 2 diabetes mellitus (T2DM) represents the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESKD), and diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes. Despite advances in the nephroprotective treatment of T2DM, DKD remains the most common complication, driving the need for renal replacement therapies (RRT) worldwide, and its incidence is increasing. Until recently, prevention of DKD progression was based around strict blood pressure (BP) control, using renin–angiotensin system blockers that simultaneously reduce BP and proteinuria, adequate glycemic control and control of cardiovascular risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a new class of anti-hyperglycemic drugs shown to improve cardiovascular and renal events in DKD. In this regard, GLP-1RA offer the potential for adequate glycemic control in multiple stages of DKD without an increased risk of hypoglycemia, preventing the onset of macroalbuminuria and slowing the decline of glomerular filtration rate (GFR) in diabetic patients, also bringing additional benefit in weight reduction, cardiovascular and other kidney outcomes. Results from ongoing trials are pending to assess the impact of GLP-1RA treatments on primary kidney endpoints in DKD.

scholarly journals Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1143
Author(s):  
Midori Sakashita ◽  
Tetsuhiro Tanaka ◽  
Reiko Inagi
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Stress Responses ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Therapeutic Agents ◽  
Metabolic Changes ◽  
Diabetic Kidney ◽  
Glucose Levels ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

scholarly journals Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease

2021 ◽  
Author(s):  
Alberto Ortiz ◽  
Charles J Ferro ◽  
Olga Balafa ◽  
Michel Burnier ◽  
Robert Ekart ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Failure ◽  
Mineralocorticoid Receptor ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Cardiovascular Death ◽  
Mineralocorticoid Receptor Antagonists ◽  
Receptor Antagonists ◽  
Diabetic Kidney

Abstract Diabetic kidney disease develops in about 40% of patients with diabetes and is the commonest cause of chronic kidney disease worldwide. Patients with chronic kidney disease, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular death. The use of renin-angiotensin system blockers to reduce the incidence of kidney failure in patients with diabetic kidney disease dates back to studies that are now 20 or more years old. During the last few years sodium-glucose co-transporter-2 inhibitors have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with renin-angiotensin system blockers and sodium-glucose co-transporter-2 inhibitors, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of cardiovascular death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists reduce albuminuria and surrogate markers of cardiovascular disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of diabetic kidney disease and the incidence of cardiovascular events with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of mineralocorticoid receptor antagonists, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic chronic kidney disease.

scholarly journals Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

2021 ◽  
Vol 10 (10) ◽  
pp. 2046
Author(s):  
Goren Saenz-Pipaon ◽  
Saioa Echeverria ◽  
Josune Orbe ◽  
Carmen Roncal
Keyword(s):  
Kidney Disease ◽  
Extracellular Vesicles ◽  
Diabetic Kidney Disease ◽  
Current Knowledge ◽  
Developed Countries ◽  
Disease Diagnosis ◽  
Renal Diseases ◽  
Diabetic Kidney ◽  
Glucose Levels ◽  
Stage Renal Disease

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

scholarly journals Proteoglycans contribute to the functional integrity of the glomerular endothelial cell surface layer and are regulated in diabetic kidney disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alina Khramova ◽  
Roberto Boi ◽  
Vincent Fridén ◽  
Anna Björnson Granqvist ◽  
Ulf Nilsson ◽  
...  
Keyword(s):  
Surface Layer ◽  
Kidney Disease ◽  
Cell Surface ◽  
Diabetic Kidney Disease ◽  
Exchange Chromatography ◽  
Diabetic Kidney ◽  
Endothelial Cell Surface ◽  
Filtration Barrier ◽  
Essential Components

AbstractAll capillary endothelia, including those of the glomeruli, have a luminal cell surface layer (ESL) consisting of glycoproteins, glycolipids, proteoglycans (PGs) and glycosaminoglycans. Previous results have demonstrated that an intact ESL is necessary for a normal filtration barrier and damage to the ESL coupled to proteinuria is seen for example in diabetic kidney disease (DKD). We used the principles of ion exchange chromatography in vivo to elute the highly negatively charged components of the ESL with a 1 M NaCl solution in rats. Ultrastructural morphology and renal function were analyzed and 17 PGs and hyaluronan were identified in the ESL. The high salt solution reduced the glomerular ESL thickness, led to albuminuria and reduced GFR. To assess the relevance of ESL in renal disease the expression of PGs in glomeruli from DKD patients in a next generation sequencing cohort was investigated. We found that seven of the homologues of the PGs identified in the ESL from rats were differently regulated in patients with DKD compared to healthy subjects. The results show that proteoglycans and glycosaminoglycans are essential components of the ESL, maintaining the permselective properties of the glomerular barrier and thus preventing proteinuria.

scholarly journals Therapeutic Strategies for Diabetic Kidney Disease

Diabetology ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 31-35
Author(s):  
Keiichiro Matoba
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Intensive Therapy ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Hemodynamic Changes ◽  
Diabetic Kidney ◽  
Global Epidemic ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD) is a global epidemic leading to end-stage renal disease (ESRD) and susceptibility to cardiovascular disease, with few therapeutic interventions. A hallmark of DKD is the activation of the renin-angiotensin-aldosterone system and hemodynamic changes in glomerulus. Although intensive therapy with agents that targets those abnormalities lowers the risk of DKD progression, it does not completely abolish the risk of ESRD and cardiovascular events. Recent studies have illustrated the importance of renal inflammation, oxidative stress, and activated Rho-associated protein kinase (ROCK) signaling as essential pathogenesis for the development of DKD. In this commentary, these topics will be discussed.

Diabetic kidney disease in thedb/dbmouse

2003 ◽  
Vol 284 (6) ◽  
pp. F1138-F1144 ◽  
Author(s):  
Kumar Sharma ◽  
Peter McCue ◽  
Stephen R. Dunn
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Mouse Model ◽  
Renal Disease ◽  
Mouse Models ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Matrix Expansion ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

Abstract 016: Profound and Sustained Amplification of Circulating ACE2 Activity Does Not Protect Diabetic Mice from Kidney Disease

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Minghao Ye ◽  
Ahmed M Khattab ◽  
Yashpal Kanwar ◽  
Mark Osborn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Over Expression ◽  
Akita Mice

ACE2 is a monocarboxypeptidase that by converting AngII to Ang1-7 should down-regulate the renin-angiotensin system and therefore provide a means to therapeutically target diabetic kidney disease, a condition where the kidney RAS is overactive. Previous work indicated that soluble human recombinant (r)ACE2 administration for 4 weeks attenuated kidney injury in diabetic Akita mice. Whether such effect of rACE2 can be confirmed and attributed to augmented ACE2 activity is uncertain because chronic use of human rACE2 in mice induces immunogenicity and the development of antibodies that neutralize serum ACE2 activity. To examine the effect of chronic amplification of circulating ACE2 on kidney injury caused by STZ-induced diabetes and to circumvent the immunogenicity arising from xenogeneic ACE2, ACE2 of mouse origin was administered to mice using either daily i.p. injections (1 mg/kg) of mrACE2 for 4 weeks or after 20 weeks of ACE2 mini-circle (MC) (10-30ug/mouse) administration. MC provides a form of gene delivery that is resistant to gene silencing and, in addition, greatly optimizes long-term in vivo overexpression of proteins of interest. ACE2MC resulted in a profound and sustained increase in serum ACE2 activity (2.4±0.3 vs. 497±135 RFU/ul/hr, p<0.01) but kidney ACE2 activity was unchanged (17.4±1.3 vs. 19.0±0.8 RFU/ug prot/hr). mACE2-treated mice injected with STZ developed diabetes similar to sham mice injected with STZ. Systolic BP was not different between non-diabetic mice, sham STZ-mice, and STZ-mice receiving mACE2 by either i.p. mrACE2 or ACE2MC. Urinary albumin was similarly increased in sham STZ-mice and in STZ-mice receiving mACE2. Glomerular mesangial score and glomerular cellularity were both increased to a similar extent in sham STZ-mice and in STZ-mice with mACE2 administration, as compared to non-diabetic controls. In conclusion, profound and long-term augmentation of ACE2 activity confined to the circulation is not sufficient to attenuate glomerular pathology and albuminuria in STZ-induced diabetic kidney disease probably because of lack of kidney delivery of ACE2. Strategies to achieve over-expression of ACE2 at the kidney level are needed to demonstrate a beneficial effect of this enzyme on diabetic kidney disease.

scholarly journals MMP-10 is Increased in Early Stage Diabetic Kidney Disease and can be Reduced by Renin-Angiotensin System Blockade

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
José María Mora-Gutiérrez ◽  
José Antonio Rodríguez ◽  
María A. Fernández-Seara ◽  
Josune Orbe ◽  
Francisco Javier Escalada ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Renin Angiotensin System ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Angiotensin System ◽  
Diabetic Kidney ◽  
Renin Angiotensin

AbstractMatrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD.

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