Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice.

Rac1, a GTPase of the Rho subfamily, has a crucial role in cytoskeletal architecture, as well as the regulation of cell migration and growth. However, renal injury in mice with podocyte-specific deletion of Rac1 has yet to be elucidated fully due to conflicting findings. Herein, we identified a possible role for Rac1 in podocytes of streptozotocin- (STZ) induced diabetic mice. The urinary albumin/creatinine ratio (ACR) in the knockout (KO) group was significantly higher than that in the wild type (WT) group at any week of age. A more marked ACR increase was observed in STZ/KO group than STZ/WT group, although ACR did increase with weeks of age in both diabetic groups. The kidney sections from diabetic mice revealed a glomerular hypertrophy with mesangial expansion, but there was no appreciable difference in glomerular findings under a light microscope between STZ/WT and STZ/KO mice. However, an electron microscopy analysis revealed that regardless of the presence or absence of diabetes, both KO (KO and STZ/KO) groups had a higher rate of foot process effacement compared with both WT (WT and STZ/WT) groups. The expression levels of the slit diaphragm protein, podocin, was reduced with the induction of diabetes, and the levels in the STZ/KO group experienced a further reduction compared with the STZ/WT group. The number of WT1-positive cells in the STZ/KO group was more significantly decreased than that in the other three groups. In contrast, the numbers of cleaved caspase 3- and TUNEL-positive cells in the glomeruli of the STZ/KO group were more increased than those in the STZ/WT group. Thus, this study provides evidence that podocyte-specific deletion of Rac1 results in morphological alteration in podocytes, and that the induction of apoptosis or decreased expression of the slit diaphragm proteins by hyperglycemic stimuli are associated with the progression of diabetic nephropathy.

Ishizaka M ，Gohda T ，Takagi M ，Omote K ，Sonoda Y ，Oliva Trejo JA ，Asao R ，Hidaka T ，Asanuma K ，Horikoshi S ，Tomino Y ... -  《-》

Mesenchymal stem cells ameliorate podocyte injury and proteinuria in a type 1 diabetic nephropathy rat model.

Mesenchymal stem cells (MSC) attenuate albuminuria and preserve normal renal histology in diabetic mice. However, the effects of MSC on glomerular podocyte injury remain uncertain. The aim of this study was to evaluate the effects of MSC on podocyte injury in streptozotocin (STZ)-induced diabetic rats. Thirty days after diabetes induction by STZ injection (65 mg/kg, intraperitoneally) in Sprague-Dawley rats, the diabetic rats received medium or 2 × 10(6) enhanced green fluorescent protein-labeled MSC via the renal artery. In vivo tracking of MSC was followed by immunofluorescence analysis. Diabetes-related physical and biochemical parameters were measured on day 60 after the MSC infusion. The expression of podocyte markers (nephrin and podocin), podocyte survival factors (VEGF and BMP-7), and the ultrastructural pathology of podocytes were also assessed. MSC were only detected in the glomeruli from the left kidney receiving MSC infusion. Compared with medium-treated diabetic rats, rats treated with MSC showed a suppressed increase in kidney weight, kidney to body weight index, creatinine clearance rate, and urinary albumin to creatinine ratio; however, the treatment had no effect on blood glucose or body weight levels. Furthermore, the MSC treatment reduced the loss of podocytes, effacement of foot processes, widening of foot processes, thickening of glomerular basal membrane (GBM), and loss of glomerular nephrin and podocin. Most important, MSC-injected kidneys expressed higher levels of BMP-7 but not of VEGF. Our results clearly demonstrated that intra-arterial administration of MSC prevented the development of albuminuria as well as any damage to or loss of podocytes, though there was no improvement in blood sugar levels. The protective effects of MSC may be mediated in part by increasing BMP-7 secretion.

Wang S ，Li Y ，Zhao J ，Zhang J ，Huang Y ... -  《-》

Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice.

Lv Z ，Hu M ，Fan M ，Li X ，Lin J ，Zhen J ，Wang Z ，Jin H ，Wang R ... -  《Cell Death & Disease》

Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.

Blattner SM ，Hodgin JB ，Nishio M ，Wylie SA ，Saha J ，Soofi AA ，Vining C ，Randolph A ，Herbach N ，Wanke R ，Atkins KB ，Gyung Kang H ，Henger A ，Brakebusch C ，Holzman LB ，Kretzler M ... -  《-》

The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats.

Kim SH ，Jang YW ，Hwang P ，Kim HJ ，Han GY ，Kim CW ... -  《-》