αB-Crystallin Protects Against Cisplatin-Induced Nephrotoxicity by Modulating Apoptosis In Vivo and In Vitro

Cisplatin (CP) chemotherapy is limited by nephrotoxicity, primarily involving tubular epithelial cell apoptosis. αB-crystallin (CryAB) is a small heat shock protein that plays a cytoprotective role in stressed kidneys but can also promote tumor progression. Its precise role and molecular mechanisms in CP-induced kidney injury remain largely unclear. This study highlighted the function of CryAB and its regulatory pathways in CP nephrotoxicity by employing in vitro models of rat renal tubular epithelial cells (NRK-52E) with CryAB gene knockdown/overexpression, and in vivo models of CryAB knockout/wild-type mice, followed by CP treatment. Apoptosis and key signaling pathways (NF-κB, MAPK, AKT) were evaluated in this study. The results indicated that CP treatment (20 µM) significantly upregulated CryAB expression in renal cells (p < 0.01) and triggered both apoptosis and MAPK activation. CryAB deficiency sensitized cells and mice to CP, exacerbating renal dysfunction, tubular injury, and apoptosis, as evidenced by increased Bax, cyt c release, and caspase-3 cleavage. Conversely, CryAB overexpression attenuated these effects. Furthermore, our findings suggest that the lack of CryAB favors the cytoplasmic retention of NF-κB, and that CryAB status can influence MAPK signaling, pointing to a potential regulatory loop. Additionally, CP-induced AKT phosphorylation was diminished in CryAB-deficient models. Therefore, CryAB may exert a cytoprotective role in CP nephrotoxicity, potentially mitigating tubular apoptosis by modulating the mitochondrial apoptotic pathway, supporting NF-κB-mediated survival signaling, and cross-talking with MAPK and AKT pathways. Our findings suggest that CryAB serves as an important regulator of renal cell fate and a potential therapeutic target for mitigating CP-induced kidney injury.