semaxinib and Diabetic-Nephropathies

To analyze the correlation between the expressions of vascular endothelial growth factor (VEGF) and transient receptor potential canonical 6 (TRPC6) and their role in podocyte injury in rats with diabetic nephropathy.. Forty SD rats with diabetic nephropathy induced by intraperitoneal injection of 65 mg/kg streptozotocin were randomized equally into 5 groups, including a diabetic nephropathy model group and 4 treatment groups, with 8 normal SD rats as the normal control group. In the 4 treatment groups, the rats received intraperitoneal injections with SU5416 at 5 mg/kg or 10 mg/kg twice a week or with LY294002 at 1 mg/kg or 2 mg/kg once daily for 8 weeks. Blood glucose, serum creatinine, blood urea nitrogen, and 24-h urinary protein levels of the rats were detected at different time points, and the pathologies in the renal tissue were observed using HE staining, PAS staining and immunohistochemistry. The expressions of VEGF, nephrin, and TRPC6 at mRNA and protein levels were detected using RT-PCR and Western blotting.. Compared with normal control rats, the diabetic rats showed significantly increased fasting blood glucose, serum creatinine, blood urea nitrogen and 24-h urinary protein levels with decreased expressions of nephrin mRNA and protein (P<0.05) and increased expressions of VEGF and TRPC6 (P<0.05). Compared with the untreated diabetic rats, the rats with SU5416 treatment showed increased 24-h urinary protein, urea nitrogen, and nephrin expression and decreased TRPC6 expression without significant changes in fasting blood glucose, serum creatinine, or VEGF expression. The rats treated with LY294002 showed decreased 24-h urinary protein and TRPC6 expression without significant changes in fasting blood glucose, serum creatinine, urea nitrogen, or expressions of nephrin and VEGF.. The regulatory effect of VEGF on TRPC6 can be blocked by inhibiting VEGFR-2 or blocking PI3K/Akt signaling pathway.

Topics: Animals; Chromones; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Indoles; Kidney; Membrane Proteins; Morpholines; Podocytes; Pyrroles; Random Allocation; Rats; Rats, Sprague-Dawley; TRPC Cation Channels; Vascular Endothelial Growth Factor A

To explore the effect of VEGF inhibitor SU5416 on podocytopathy of rats with type I diabetic nephropathy.. Thirty male SD rats were randomly divided into three groups: normal control group(NC), diabetic nephropathy group(DN) and diabetic nephropathy treated with SU5416 group(SU5416). Rats with DN were induced by STZ. At the end of 8 weeks after SU5416 treatment, body weight (BW), kidney weight (KW), 24 h urine albuminuria excretion rate(24 h UAER), plasma glucose and creatinine were detected respectively. Renal morphology were stained with periodic acid-Schiff (PAS). And the expression of podocyte-specific genes nephrin and podocin were detected by immunofluorescence. The mRNA levels of genes and VEGF were assessed by real time-PCR respectively.. Compared with NC group, DN rats'BW were decreased but the KW were increased, and the levels of blood glucose, creatinine, 24 h UAER and kidney cortex VEGF mRNA were significantly higher. The expression of nephrin and podocin were decreased(P<0.05), and GBM thickening and mesangial matrix expansion were developed. Treatment with SU5416 leads to a marked decrease of KW and the level of 24 h UAER. Concurrently, the expressions of nephrin and podocin were revert partly in response to SU5416(P<0.05), and pathological changes were successfully ameliorated. However, the KW, glucose, creatinine and the level of VEGF mRNA were not significantly affected by SU5416 treatment(P>0.05).. VEGF-R inhibitor SU5416 can obviously ameliorate albuminuria and histologic changes, and restore the expression of podocyte-specific genes nephrin and podocin in DN rats, suggesting that VEGF-R inhibitor is beneficial for the repair of podocytes in DN, which might be an important adjunct for podocytopathy therapy.

Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Gene Expression Regulation; Indoles; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Podocytes; Protein Kinase Inhibitors; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Vascular Endothelial Growth Factor; RNA, Messenger; Vascular Endothelial Growth Factor A

For investigation of how the vascular endothelial growth factor (VEGF) system participates in the pathogenesis of diabetic kidney disease, type 2 diabetic db/db and control db/m mice were treated intraperitoneally with vehicle or 2 mg/kg of a pan-VEGF receptor tyrosine kinase inhibitor, SU5416, twice a week for 8 wk. Efficacy of SU5416 treatment in the kidney was verified by the inhibition of VEGF receptor-1 phosphorylation. Glomerular VEGF immunostaining, normally increased in diabetes, was unaffected by SU5416. Plasma creatinine did not change with diabetes or SU5416 treatment. The primary end point of albuminuria increased approximately four-fold in the diabetic db/db mice but was significantly ameliorated by SU5416. Correlates of albuminuria were investigated. Diabetic glomerular basement membrane thickening was prevented in the SU5416-treated db/db mice, whereas mesangial matrix expansion remained unchanged by treatment. The density of open slit pores between podocyte foot processes was decreased in db/db diabetes but was partly increased toward normal by SU5416. Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416. Paradoxically, total nephrin protein by immunoblotting was increased in diabetes, pointing toward a possible dysregulation of nephrin trafficking. Diabetic albuminuria is partially a function of VEGF receptor signaling overactivity. VEGF signaling was found to affect a number of podocyte-driven manifestations such as GBM thickening, slit pore density, and nephrin quantity, all of which are associated with the extent of diabetic albuminuria. By impeding these pathophysiologic processes, VEGF receptor inhibition by SU5416 might become a useful adjunct to anti-albuminuria therapy in diabetic nephropathy.

Topics: Albuminuria; Animals; Diabetic Nephropathies; Indoles; Male; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors; Pyrroles; Vascular Endothelial Growth Factor A