Tubule-Specific RGC-32 Knockout Exhibits Direct and Progressive Aggravating Activity Against Renal Function in an Ischemia–Reperfusion Mouse Model

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Although the prevalence of acute kidney injury and chronic kidney disease remains high and effective therapeutic targets remain scarce, significant progress has been made in recent years across the following major directions: G2/M phase cell cycle arrest, DNA damage, mitochondrial dysfunction, hypoxia-inducible factor signaling, dysregulated autophagy, and epigenetic alterations. RGC-32 is abundantly expressed in all tubular segments of normal renal tissues and is primarily localized to the cytoplasm and perinuclear region of renal tubular epithelial cells. Moreover, RGC-32 is involved in cell cycle regulation as well as cell proliferation and differentiation. To explore the functional role of RGC-32 in renal repair after acute ischemia-reperfusion injury, we utilized CRISPR-Cas9 technology combined with Cre/loxP recombination to generate a novel, renal tubule-specific RGC-32 knockout mouse model and systematically characterized its phenotype. Our findings demonstrate that renal tubule-specific RGC-32 deficiency does not impair normal growth or baseline renal function but alters the distribution of peripheral blood T lymphocyte subsets; whether this alteration contributes to renal immune regulation remains to be determined by future functional studies. More importantly, upon IRI, RGC-32 knockout in renal tubules leads to significantly aggravated renal dysfunction, elevated injury markers, and a possible association with enhanced chronic fibrosis.

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