scholarly journals Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury

2011 ◽  
Vol 301 (6) ◽  
pp. F1358-F1366 ◽  
Author(s):  
Alaa S. Awad ◽  
Gilbert R. Kinsey ◽  
Konstantine Khutsishvili ◽  
Ting Gao ◽  
W. Kline Bolton ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Chemokine Receptor ◽  
Renal Injury ◽  
Diabetic Kidney Disease ◽  
Renal Tissue ◽  
Direct Role ◽  
Diabetic Kidney ◽  
Glucose Levels ◽  
Macrophage Recruitment ◽  
Monocyte Migration

Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN). C-C chemokine receptor (CCR)2 regulates monocyte/macrophage migration into injured tissues. However, the direct role of CCR2-mediated monocyte/macrophage recruitment in diabetic kidney disease remains unclear. We report that pharmacological blockade or genetic deficiency of CCR2 confers kidney protection in Ins2Akita and streptozotocin (STZ)-induced diabetic kidney disease. Blocking CCR2 using the selective CCR2 antagonist RS504393 for 12 wk in Ins2Akita mice significantly attenuated albuminuria, the increase in blood urea nitrogen and plasma creatinine, histological changes, and glomerular macrophage recruitment compared with vehicle. Furthermore, mice lacking CCR2 (CCR2−/−) mimicked CCR2 blockade by reducing albuminuria and displaying less fibronectin mRNA expression and inflammatory cytokine production compared with CCR2+/+ mice, despite comparable blood glucose levels. Bone marrow-derived monocytes from CCR2+/+ or CCR2−/− mice adoptively transferred into CCR2−/− mice reversed the renal tissue-protective effect in diabetic CCR2−/− mice as evaluated by increased urinary albumin excretion and kidney macrophage recruitment, indicating that CCR2 is not required for monocyte migration from the circulation into diabetic kidneys. These findings provide evidence that CCR2 is necessary for monocyte/macrophage-induced diabetic renal injury and suggest that blocking CCR2 could be a novel therapeutic approach in the treatment of DN.

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 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.

Targeted deletion of NADPH-Oxidase Nox4 from proximal tubules is dispensable for diabetic kidney disease development

2020 ◽  
Author(s):  
Vicki Thallas-Bonke ◽  
Sih Min Tan ◽  
Runa S Lindblom ◽  
Matthew Snelson ◽  
Cesare Granata ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Nadph Oxidase ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Proximal Tubules ◽  
Disease Development ◽  
Diabetic Kidney ◽  
Genetic Ablation ◽  
Proximal Tubular

Abstract Background The NADPH oxidase isoform, Nox4, mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in diabetic kidney disease within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. Methods We generated a proximal tubular specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the Sglt2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. Results Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of diabetic kidney disease including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKOSTZ mice compared to Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. Conclusion Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence diabetic kidney disease development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes.

scholarly journals Urinary Periostin as an Early Predictor of Renal Injury in Diabetic Kidney Disease: A Tertiary Centre Experience

2019 ◽  
Vol 9 (3) ◽  
pp. 100-104
Author(s):  
Munna Lal Patel ◽  
Rekha Sachan ◽  
Durgesh Pushkar ◽  
Shyam Chand Chaudhary ◽  
Kamlesh Kumar Gupta
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Tertiary Centre ◽  
Early Predictor

scholarly journals Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility

Diabetes ◽  
2019 ◽  
Vol 69 (1) ◽  
pp. 83-98 ◽  
Author(s):  
Sih Min Tan ◽  
Mark Ziemann ◽  
Vicki Thallas-Bonke ◽  
Matthew Snelson ◽  
Vinod Kumar ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Complement C5a

scholarly journals The incretin pathway as a therapeutic target in diabetic kidney disease: a clinical focus on GLP-1 receptor agonists

2019 ◽  
Vol 10 ◽  
pp. 204201881986539 ◽  
Author(s):  
Michaël J. B. van Baar ◽  
Annemarie B. van der Aart ◽  
Klaas Hoogenberg ◽  
Jaap A. Joles ◽  
Hiddo J. L. Heerspink ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Treatment Options ◽  
Diabetic Kidney ◽  
Receptor Agonists ◽  
Glucose Levels ◽  
Glucagon Like Peptide ◽  
New Treatment ◽  
End Stage ◽  
Increases In Risk

Diabetic kidney disease (DKD) remains the main cause for chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Both CKD and ESKD lead to major increases in risk of cardiovascular disease and death in people with diabetes. Despite optimal management of lifestyle, glucose levels and hypertension, residual risk remains high, indicating that additional therapies to mitigate the burden of the disease are desired. In past decades, new treatment options for the management of diabetes have emerged, of which some have showed promising renoprotective potential. This review discusses current understanding of the renal effects of glucagon-like peptide receptor agonists and their potential use in prevention and treatment of DKD.

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