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Deletion of the Formin, Diaph1, Protects from Structural and Functional Abnormalities in the Murine Diabetic Kidney.

Manigrasso, Michaele B; Friedman, Richard A; Ramasamy, Ravichandran; D'Agati, Vivette D; Schmidt, Ann Marie.
Artigo em Inglês | MEDLINE | ID: mdl-30132346
Diaphanous 1 (DIAPH1), a member of the formin family, binds to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE) and is required for RAGE signal transduction. Experiments employing genetic over-expression or deletion of Ager (the gene encoding RAGE) or its pharmacological antagonism, implicate RAGE in the pathogenesis of diabetes-associated nephropathy. We hypothesized that DIAPH1 contributes to pathological and functional derangements in the kidneys of diabetic mice. Here, we show that DIAPH1 is expressed in the human and murine diabetic kidney, at least in part in the tubulointerstitium and glomerular epithelial cells, or podocytes. To test the premise that DIAPH1 is linked to diabetes-associated derangements in the kidney, we rendered male mice globally devoid of Diaph1 or wild-type controls (C57BL/6 background), diabetic with streptozotocin. Control mice received equal volumes of citrate buffer. After six months of hyperglycemia, diabetic mice devoid of Diaph1 displayed significantly reduced mesangial sclerosis, podocyte effacement, glomerular basement thickening, and urine albumin/creatinine ratio, compared to diabetic mice expressing Diaph1. Analysis of whole kidney cortex revealed that deletion of Diaph1 in diabetic mice significantly reduced expression of genes linked to fibrosis and inflammation. In glomerular isolates, expression of two genes linked to podocyte stress, Gas1 and Cd36, was significantly attenuated in diabetic mice devoid of Diaph1 vs. controls, in parallel with significantly higher levels of Nes mRNA, a podocyte marker. Collectively, these data implicate DIAPH1 in the pathogenesis of diabetes-associated nephropathy and suggest that RAGE/DIAPH1 is a logical target for therapeutic intervention in this disorder.
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