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The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-\u03b2 (TGF-\u03b2) and vascular endothelial growth factor (VEGF) systems. TGF-\u03b21 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman\u2019s capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.<\/jats:p>","DOI":"10.2337\/diabetes.54.6.1626","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T14:04:22Z","timestamp":1173189862000},"page":"1626-1634","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":464,"title":["From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease"],"prefix":"10.2337","volume":"54","author":[{"given":"Gunter","family":"Wolf","sequence":"first","affiliation":[{"name":"Department of Internal Medicine (Klinik fu\u0308r Innere Medizin III), University Hospital, Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheldon","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renal-Electrolyte and Hypertension Division, Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuad N.","family":"Ziyadeh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renal-Electrolyte and Hypertension Division, Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031209103520500_R1","unstructured":"Kimmelstiel P, Wilson C: Intercapillary lesions in the glomeruli of the kidney. 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