Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1α

Abstract

The small GTPase Rho and its effector Rho-kinase are involved in the pathogenesis of diabetic nephropathy. Accumulating evidence shows that hypoxia-inducible factor-1α (HIF-1α) is a key regulator of renal sclerosis under diabetic conditions. However, the interactions of Rho-kinase and HIF-1α in the development of renal dysfunction have not been defined. Here, we assessed whether Rho-kinase blockade attenuates HIF-1α induction and the subsequent fibrotic response using type 2 diabetic mice and cultured mesangial cells. Fasudil, a Rho-kinase inhibitor, reduced urinary albumin excretion, mesangial matrix expansion, and the expression of fibrotic mediators in db/db mice. Mechanistically, HIF-1α accumulation and the expression of its target genes that contribute to diabetic glomerulosclerosis were also prevented by fasudil in the renal cortex. In mesangial cells, Rho/Rho-kinase signaling was activated under hypoxic conditions. Further in vitro studies showed that pharmacological and genetic inhibition of Rho-kinase promoted proteasomal HIF-1α degradation, which subsequently suppressed HIF-1-dependent profibrotic gene expression by upregulation of prolyl hydroxylase 2. Thus, we found a previously unrecognized renoprotective mechanism for the effects of Rho-kinase inhibition and this could be a potential therapeutic target for the treatment of diabetic nephropathy.

Dyslipidemia in diabetic nephropathy

“…Finally, we have shown that Rhokinase blockade attenuates other microvascular complications such as diabetic retinopathy [56] and neuropathy [57], as well as atherosclerosis [58]. Importantly, the effect of Rho-kinase inhibitors on diabetic complications is independent of glucose and blood pressure [51,53]. These findings suggest that Rho-kinase could be a comprehensive therapeutic target that governs both microvascular and macrovascular complications.…”

“…Although HIF-1α was shown to be upregulated in the renal cortex of diabetic mice (db/db mice), Rho-kinase blockade attenuates HIF-1α induction and the subsequent fibrotic response under diabetic conditions [53]. It was also suggested that this change in HIF-1α was partly due to the regulation of proteasomal degradation of HIF-1α by Rho-kinase [53].…”

“…We further investigated the effect of Rhokinase inhibition on hypoxia inducible factor (HIF)-1α, a transcriptional factor which has been implicated in the pathogenesis of DN [52]. Although HIF-1α was shown to be upregulated in the renal cortex of diabetic mice (db/db mice), Rho-kinase blockade attenuates HIF-1α induction and the subsequent fibrotic response under diabetic conditions [53]. It was also suggested that this change in HIF-1α was partly due to the regulation of proteasomal degradation of HIF-1α by Rho-kinase [53].…”

Rho-Kinase Activation in Patients With Heart Failure

“…We consider that the blood vessel and the kidney are also important for HF development, especially in relation to Rho-kinase activation. 45,46 Conclusions Rho-kinase is systemically activated in patients with HF, suggesting that Rho-kinase could be a new therapeutic target of CHF, and that Rho-kinase activity in circulating leukocytes may be a novel biomarker of the disorder.…”

Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

“…Recent studies have indicated that RhoA/ROCK signaling is an important contributor to diabetic nephropathy [9,10] . Fasudil, a relatively specific ROCK inhibitor, has nephroprotective actions during experimental diabetic nephropathy [11][12][13] . The possible mechanisms include the attenuation of diabetes-induced increases in renal TGF-β, CTGF and extracellular matrix (ECM) protein expression resulting in slower glomerulosclerosis and interstitial fibrosis development.…”