Harnessing ROCK biology to revolutionize diabetic nephropathy: decoding mechanisms, designing therapies

Abstract Diabetes remains a major cause of kidney failure globally, presenting substantial challenges to healthcare systems worldwide. Although significant progress has been made in understanding its pathogenesis, residual risks persist despite current therapies. Emerging evidence underscores the pivotal role of small GTPases—particularly Rho and Rho-associated coiled-coil-containing protein kinase (ROCK)—in the progression of diabetic nephropathy. This comprehensive review consolidates current knowledge on the distinct pathophysiological roles of the ROCK isoforms, ROCK1 and ROCK2, in diabetic nephropathy, drawing on recent insights from both genetic and pharmacological studies. We explore how ROCK signaling interfaces with key pathological mechanisms, including podocyte injury, glomerulosclerosis, tubular dysfunction, and metabolic disturbances. Particular emphasis is placed on isoform-specific functions: ROCK1 primarily regulates AMP-activated protein kinase-mediated fatty acid metabolism and mitochondrial dynamics, while ROCK2 modulates peroxisome proliferator-activated receptor α signaling and inflammatory responses. Furthermore, we discuss the translational implications of these findings, focusing on the therapeutic potential of ROCK inhibitors in chronic kidney disease (CKD) with diabetes and related disorders, such as focal segmental glomerulosclerosis, as well as their impact on electrolyte balance. By integrating molecular insights with clinical considerations, this review provides a framework for developing targeted strategies to halt the CKD progression in people with diabetes.