Deletion of the formin Diaph1 protects from structural and functional abnormalities in the murine diabetic kidney.
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 overexpression 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. 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 ( Diaph1-/-) or wild-type controls (C57BL/6 background) diabetic with streptozotocin. Control mice received equal volumes of citrate buffer. After 6 mo of hyperglycemia, diabetic Diaph1-/- mice displayed significantly reduced mesangial sclerosis, podocyte effacement, glomerular basement thickening, and urinary albumin-to-creatinine ratio compared with 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, growth arrest-specific 1 ( Gas1) and cluster of differentiation 36 ( Cd36), was significantly attenuated in diabetic Diaph1-/- mice compared with controls, in parallel with significantly higher levels of nestin (Nes) mRNA, a podocyte marker. Collectively, these data implicate DIAPH1 in the pathogenesis of diabetes-associated nephropathy and suggest that the RAGE-DIAPH1 axis is a logical target for therapeutic intervention in this disorder.
['Manigrasso|Michaele B|MB|', 'Friedman|Richard A|RA|', 'Ramasamy|Ravichandran|R|', "D'Agati|Vivette|V|", 'Schmidt|Ann Marie|AM|']
D048868:Adaptor Proteins, Signal Transducing D000419:Albuminuria D000818:Animals D018955:CD36 Antigens D002352:Carrier Proteins D016022:Case-Control Studies D018797:Cell Cycle Proteins D003921:Diabetes Mellitus, Experimental D003928:Diabetic Nephropathies D000080865:Formins D058851:GPI-Linked Proteins D017353:Gene Deletion D006801:Humans D007668:Kidney D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D064231:Nestin D000067759:Receptor for Advanced Glycation End Products D015398:Signal Transduction D013311:Streptozocin
DIAPH1 kidney glycation RAGE podocyte