Role of kidney ADP-ribosyl cyclase in diabetic nephropathy

The role of ADP-ribosyl cyclases (ADPR-cyclases) in diabetic nephropathy was investigated. ADPR-cy- clases synthesize cADP-ribose (cADPR), a Ca ²⁺-mobilizing second messenger, and are stimulated by G protein-coupled receptors. We have previously reported that ADPR-cyclases can be activated by ANG II and showed that a specific kidney ADPR-cyclase inhibitor, 4,4′-dihydroxya-zobenzene (DHAB), can protect ANG II-mediated mesangial cell growth (Kim SY, Gul R, Rah SY, Kim SH, Park SK, Im MJ, Kwon HJ, Kim UH. Am J Physiol Renal Physiol 294: F982-F989, 2008). In this study, we examined the preventive effect of DHAB on glomerular injury in streptozotocin (STZ)-induced diabetic mice. Male mice were randomly assigned to normal control and diabetic groups of comparable age. A diabetic group received 45 μg/kg of DHAB for 6 wk via daily intraperitoneal injections. Several nephropathy parameters were improved in the DHAB-treated diabetic group compared with the diabetic group, including urinary albumin (diabetic, 44.6 ± 5.1 vs. treated, 33.9 ± 3.9 μg/day), creatinine clearance (diabetic, 0.72 ± 0.03 vs. treated, 0.83 ± 0.04 ml· min^-1 · 100 g ^-1), ratio of kidney to body weight (diabetic, 2.5 ± 0.04 vs. treated, 1.4 ± 0.04), and mesangial matrix expansion (diabetic, 13.9 ± 2.2 vs. treated, 8.5 ± 2.0%). These results indicate that kidney function in STZ-induced diabetes was improved by DHAB administration. Furthermore, DHAB inhibited phosphorylation of Akt and nuclear factor of activated T cell 3 nuclear translocation, as well as ADPR-cyclase activity and cADPR production, which were increased in the kidneys of the diabetic group. In addition, DHAB treatment decreased fibrosis marker protein expression and glomerular hypertrophy in the diabetic kidney. These findings indicate a crucial role that ADPR-cyclase signaling plays in the renal pathogenesis of diabetes and provide a therapeutic tool for the treatment of renal diseases.