Matricellular protein SMOC2 safeguards tubular integrity in acute kidney injury via integrin β3-dependent inhibition of CCND1-CDK4/6 axis

Tubular injury during acute kidney injury (AKI) is a major determinant of chronic kidney disease (CKD) progression, yet the molecular mechanisms underlying tubular protection remain incompletely understood. Here, we identify the matricellular protein SPARC-related modular calcium-binding 2 (SMOC2) as a previously unrecognized protective regulator of tubular injury. Although SMOC2 has been implicated in renal fibrosis through fibroblast activation, its role during AKI remains unknown. We show that SMOC2 expression is rapidly and robustly induced in renal tubules following exposure to aristolochic acid I (AAI) or cisplatin. Unexpectedly, SMOC2 knockout mice exhibited aggravated tubular injury, increased DNA damage and apoptosis, and worsened renal function in both AAI- and cisplatin-induced AKI models, whereas recombinant SMOC2 (rSMOC2) treatment markedly ameliorated AAI-induced tubular injury. Furthermore, in an AAI-induced AKI-to-CKD model, SMOC2 deficiency exacerbated renal fibrosis, linking early tubular protection to long-term outcomes. Mechanistically, transcriptomic profiling and biochemical analyses revealed that SMOC2 suppresses aberrant G1/S cell cycle progression by restraining the CCND1-CDK4/6 axis through its interaction with integrin β3 (ITGB3), thereby arresting tubular cells in the G1 phase and facilitating DNA repair. This interaction depends on the cooperation of multiple structural domains rather than a single motif. Notably, pharmacological inhibition of CDK4/6 with palbociclib phenocopied the protective effects of SMOC2, with post-injury treatment providing superior protection, thus defining a druggable downstream pathway. Collectively, our findings uncover a previously unappreciated cytoprotective role of SMOC2 in AKI and establish the SMOC2-ITGB3-CCND1-CDK4/6 signaling axis as a potential therapeutic target to prevent AKI progression and its transition to CKD.