Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice

Zhang, Hongyu; Schin, Mary Lee A.; Saha, Jharna; Burke, Kathleen A.; Holzman, Lawrence B.; Filipiak, Wanda E.; Saunders, Thomas L.; Xiang, Minghui; Heilig, Charles W.; Brosius, Frank C.

doi:10.1152/ajprenal.00021.2010

Cited by 43 publications

(39 citation statements)

References 41 publications

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“…Mesangial area was expressed quantitatively by calculating the percentage of the total glomerular area that was PAS positive. 45,46 Fifteen glomerular tufts per animal were chosen randomly for analysis.…”

Section: Glomerular Morphometrymentioning

confidence: 99%

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Mohamed

Jayakumar

Chen

et al. 2016

Journal of the American Society of Nephrology

105

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Diabetes is the leading cause of kidney failure, accounting for .45% of new cases of dialysis. Diabetic nephropathy is characterized by inflammation, fibrosis, and oxidant stress, pathologic features that are shared by many other chronic inflammatory diseases. The cytokine IL-17A was initially implicated as a mediator of chronic inflammatory diseases, but recent studies dispute these findings and suggest that IL-17A can favorably modulate inflammation. Here, we examined the role of IL-17A in diabetic nephropathy. We observed that IL-17A levels in plasma and urine were reduced in patients with advanced diabetic nephropathy. Type 1 diabetic mice that are genetically deficient in IL-17A developed more severe nephropathy, whereas administration of low-dose IL-17A prevented diabetic nephropathy in models of type 1 and type 2 diabetes. Moreover, IL-17A administration effectively treated, prevented, and reversed established nephropathy in genetic models of diabetes. Protective effects were also observed after administration of IL-17F but not IL-17C or IL-17E. Notably, tubular epithelial cell-specific overexpression of IL-17A was sufficient to suppress diabetic nephropathy. Mechanistically, IL-17A administration suppressed phosphorylation of signal transducer and activator of transcription 3, a central mediator of fibrosis, upregulated anti-inflammatory microglia/macrophage WAP domain protein in an AMP-activated protein kinasedependent manner and favorably modulated renal oxidative stress and AMP-activated protein kinase activation. Administration of recombinant microglia/macrophage WAP domain protein suppressed diabetes-induced albuminuria and enhanced M2 marker expression. These observations suggest that the beneficial effects of IL-17 are isoform-specific and identify low-dose IL-17A administration as a promising therapeutic approach in diabetic kidney disease. CKDs such as diabetic nephropathy are a serious public health problem. In the United States, .20 million adults have CKD, and 20%-40% of patients with diabetes develop nephropathy. The financial burden of diabetes is estimated to be $245 billion per year in the United States alone, and the cost for diabetic nephropathy is estimated to be .$20 billion per year. While intensive insulin therapy and control of hypertension can delay the onset of diabetic nephropathy, 1-3 these therapies cannot reverse CKD once it has developed. Recently, feeding mice a strictly ketogenic diet (5% carbohydrate, 8% protein, 87% fat) reversed a mild form of nephropathy. 4 Although implementing such an extreme diet

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Section: Glomerular Morphometrymentioning

confidence: 99%

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Mohamed

Jayakumar

Chen

et al. 2016

Journal of the American Society of Nephrology

105

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“…Therefore, the discovery of a specific, reliable biomarker for podocyte injury in DN is imperative. Several studies have also focused on the production of podocyte-specific proteins in patients with DN and have attempted to detect earlier functional abnormalities in podocytes [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of podocyte-secreted angiopoietin-like-4 in diabetic nephropathy

Xiao

et al. 2014

Endocrine

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Podocyte injury plays a key role in the development of diabetic nephropathy (DN). Understanding the changes in podocyte structure and function in diabetes mellitus may lead to novel diagnostic tools and treatment strategies for DN. Albuminuria, histological alterations, and podocyte injury were detected at different time points in streptozotocin (STZ)-induced diabetic rats. Increased urinary albumin-to-creatinine ratios (ACR) and podocyte injury were significantly observed 4 weeks post-STZ injection. We determined the glomerular expression and distribution of angiopoietin-like 4 (Angptl4) by immunofluorescence and real-time PCR. Glomerular Angptl4 expression was mostly colocalized with synaptopodin, a podocyte marker, with substantial additional overlap with the glomerular basement membrane (GBM). This finding indicated that Angptl4 might be primarily secreted by podocytes and moved toward the GBM. Moreover, we observed by Western blot analysis and ELISA that the urinary Angptl4 level was gradually upregulated in both STZ-induced rats and diabetic patients with microalbuminuria and macroalbuminuria. We further found that the increased glomerular Angptl4 expression was closely related to the urinary ACR level and podocyte injury. In addition, the urinary Angptl4 expression was closely associated with albuminuria in the rats and patients with DN. This study is the first to show that podocyte-secreted Angptl4 is upregulated in DN and can be detected in urine. Angptl4 might function as a podocyte injury marker and could be a potential and novel diagnostic and therapeutic biomarker for DN.

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“…As described previously, TRPC6 channels play a critical role in maintaining podocyte structural and functional integrity, and dysfunction of the channels can cause podocyte injury, leading to advanced kidney diseases such as FSGS and diabetic nephropathy (45, 57, 88, 92, 136,137,139,162,163,194,219,232,234,235). Accumulating evidence indicates that TRPC6 expression and function in podocytes are under control of ROS.…”

Section: Regulation Of Trpc6 By Ros In Podocytesmentioning

confidence: 90%

“…Diabetic nephropathy is characterized with podocyte injury (45,92,139,162,194,232,234). Increased TRPC6 channel expression and activity have been associated with impaired podocyte structure and function (136,137,163,219,235).…”

Section: Fig 4 Diagram Depicting the Pathways Involved In Trpc6 Promentioning

confidence: 99%

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

Chaudhari

2016

Antioxidants & Redox Signaling

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Significance: Regulation of Ca 2+ signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca 2+ -conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects. Although regulation of TRPC channel function by ROS has been well described in other tissues and cell types, such as vascular smooth muscle, this important cell regulatory mechanism has not been fully reviewed in kidney cells. Recent Advances: Accumulating evidence has shown that TRPC6 is a redox-sensitive channel, and modulation of TRPC6 Ca 2+ signaling by altering TRPC6 protein expression or TRPC6 channel activity in kidney cells is a downstream mechanism by which ROS induce renal damage. Critical Issues: This review highlights how recent studies analyzing function and expression of TRPC6 channels in the kidney and their response to ROS improve our mechanistic understanding of oxidative stress-related kidney diseases. Future Directions: Although it is evident that ROS regulate TRPC6-mediated Ca 2+ signaling in several types of kidney cells, further study is needed to identify the underlying molecular mechanism. We hope that the newly identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy. Antioxid. Redox Signal. 25, 732-748.

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Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice

Cited by 43 publications

References 41 publications

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Upregulation of podocyte-secreted angiopoietin-like-4 in diabetic nephropathy

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

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