ROCK Inhibition May Stop Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and is strongly associated with cardiovascular mortality. Given the pandemic of obesity and diabetes, the elucidation of the molecular underpinnings of DKD and establishment of effective therapy are urgently required. Studies over the past decade have identified the activated renin-angiotensin system (RAS) and hemodynamic changes as important therapeutic targets. However, given the residual risk observed in patients treated with RAS inhibitors and/or sodium glucose co-transporter 2 inhibitors, the involvement of other molecular machinery is likely, and the elucidation of such pathways represents fertile ground for the development of novel strategies. Rho-kinase (ROCK) is a serine/threonine kinase that is under the control of small GTPase protein Rho. Many fundamental cellular processes, including migration, proliferation, and survival are orchestrated by ROCK through a mechanism involving cytoskeletal reorganization. From a pathological standpoint, several analyses provide compelling evidence supporting the hypothesis that ROCK is an important regulator of DKD that is highly pertinent to cardiovascular disease. In cell-based studies, ROCK is activated in response to a diverse array of external stimuli associated with diabetes, and renal ROCK activity is elevated in the context of type 1 and 2 diabetes. Experimental studies have demonstrated the efficacy of pharmacological or genetic inhibition of ROCK in the prevention of diabetes-related histological and functional abnormalities in the kidney. Through a bird’s eye view of ROCK in renal biology, the present review provides a conceptual framework that may be widely applicable to the pathological processes of multiple organs and illustrate novel therapeutic promise in diabetology.

Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes

“…The contribution of the N -acetylneuraminic acid to the pathogenesis of myocardial infarction via inflammation suggested that N -acetylneuraminic acid could contribute to the pathogenesis of DR and DKD via the inflammation. N -acetylneuraminic acid was reported to bind to the RhoA and Cdc42 and activate Rho/Rho-associated coiled-coil containing protein kinase (ROCK) signaling pathway which was involved in various biological processes including inflammation 21 , 22 . In persons with diabetes, activation of ROCK was reported for kidney 22 , retinal vessels, and retinal pigment epithelium 23 , suggesting that ROCK activation induced by N -acetylneuraminic acid could be involved in the pathogenesis of the DR and DKD.…”

EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

“…EndMT inhibition and amelioration of vascular dysfunction has been indeed observed in both diabetic mice and cell models overexpressing miR-448-3p ( Guan et al, 2020 ). A further regulatory mechanism of EndMT in diabetic nephropathy involves miR-497 and its two targets, ROCK1 and ROCK2, which belong to the rho-associated kinases (ROCKs) family and are activated in diabetes ( Kolavennu et al, 2008 ; Liu et al, 2018 ; Matoba et al, 2020 ). A recent study showed that ROCKs inhibition, following treatment with melatonin ( N -acetyl-5-methoxytryptamine), suppressed TGF-β2-induced EndMT.…”

Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

“…The Rho-kinase (ROCK) pathway represents another significant mechanism activated by hyperglycemia [ 33 ]. Rho-kinase activation is involved in the regulation of complex cellular processes while its inhibition in DKD leads to a decrease in albuminuria [ 34 ].…”