Glomerular mesangial cell and podocyte injuries in diabetic nephropathy
Open Access
- 8 October 2018
- journal article
- review article
- Published by Wiley in Nephrology
- Vol. 23 (S4), 32-37
- https://doi.org/10.1111/nep.13451
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.Keywords
Funding Information
- Chang Gung Memorial Hospital
This publication has 41 references indexed in Scilit:
- Notch in the kidney: development and diseaseThe Journal of Pathology, 2011
- Type VIII Collagen Modulates TGF-β1-induced Proliferation of Mesangial CellsJournal of the American Society of Nephrology, 2011
- TGF-β Regulates miR-206 and miR-29 to Control Myogenic Differentiation through Regulation of HDAC4Online Journal of Public Health Informatics, 2011
- Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosisProceedings of the National Academy of Sciences of the United States of America, 2010
- Modulation of Notch-1 Signaling Alleviates Vascular Endothelial Growth Factor–Mediated Diabetic NephropathyDiabetes, 2010
- Suppressors of Cytokine Signaling Abrogate Diabetic NephropathyJournal of the American Society of Nephrology, 2010
- Dickkopf-1 Promotes Hyperglycemia–Induced Accumulation of Mesangial Matrix and Renal DysfunctionJournal of the American Society of Nephrology, 2010
- Notch Signaling in the Regulation of Stem Cell Self-Renewal and DifferentiationPublished by Elsevier BV ,2010
- IHG-1 Amplifies TGF-β1 Signaling and Is Increased in Renal FibrosisJournal of the American Society of Nephrology, 2008
- Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory MechanismJournal of the American Society of Nephrology, 2007