Beyond cytoskeletal regulation: Rho-associated, coiled-coil-containing protein kinase 2 in kidney inflammation and fibrosis.

Chronic kidney disease (CKD), histologically defined by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and capillary rarefaction, represents a profound challenge in cellular pathology. This review synthesizes recent advances to position Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) as a master regulator of maladaptive cellular remodeling in CKD. We delineate the compartment-specific histopathological roles of ROCK2, demonstrating its function as a central signaling integrator that transduces mechanical, metabolic, and inflammatory stimuli into a convergent profibrotic phenotype. At the cellular level, ROCK2 activation drives podocyte foot process effacement and mesangial matrix expansion in the glomerulus, induces metabolic reprogramming and transcriptional dysregulation in tubular epithelia, disrupts endothelial junctional integrity in the microvasculature, and promotes myofibroblast transdifferentiation and immune-mediated scarring in the interstitium. Therapeutically, isoform-selective ROCK2 inhibition with agents like belumosudil demonstrates compelling efficacy in preclinical models, attenuating hallmark histopathological lesions. Translating these findings requires biomarker-driven patient stratification and innovative kidney-targeted delivery systems to maximize effectiveness and minimize systemic effects. Future research must ultrastructurally localize ROCK2 within human kidney niches, delineate its cell-type-specific effector networks, and validate its role as a therapeutic target to halt or reverse the characteristic microscopic progression of CKD.