Deletion of the formin Diaph1 protects from structural and functional abnormalities in the murine diabetic kidney

• Published in: American journal of physiology. Renal physiology Vol. 315; no. 6; pp. F1601 - F1612
• Main Authors: Manigrasso, Michaele B, Friedman, Richard A, Ramasamy, Ravichandran, D'Agati, Vivette, Schmidt, Ann Marie
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2018
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Albuminuria - genetics; Albuminuria - metabolism; Albuminuria - pathology; Albuminuria - prevention & control; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Case-Control Studies; CD36 Antigens - genetics; CD36 Antigens - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; Formins; Gene Deletion; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Humans; Kidney - metabolism; Kidney - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Nestin - genetics; Nestin - metabolism; Receptor for Advanced Glycation End Products - genetics; Receptor for Advanced Glycation End Products - metabolism; Signal Transduction; Streptozocin; glycation; DIAPH1; kidney; RAGE; podocyte
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00075.2018

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.