AZGP1 deficiency promotes chronic kidney fibrosis in aging mice.

OBJECTIVES: Chronic kidney disease (CKD) affects 10-14% of the global population and is a leading cause of death. A hallmark of CKD is renal fibrosis, characterized by excessive extracellular matrix deposition. Although our understanding of fibrogenic mechanisms has advanced, effective antifibrotic therapies are lacking. Zinc-α2-glycoprotein 1 (AZGP1) regulates extracellular matrix remodeling in multiple organs, and we previously demonstrated that loss of AZGP1 induces fibrosis in the prostate. METHODS: AZGP1 expression was analyzed in single-cell RNA sequencing data from the mouse kidney. Kidney tissues from wild-type and AZGP1-/- mice were analyzed by hematoxylin and eosin (H&E), immunohistochemistry, and picrosirius red staining. RESULTS: AZGP1 is mainly expressed in the proximal tubule epithelial cell population. AZGP1-deficient (AZGP1-/-) mice exhibited progressive renal fibrosis with age. While no interstitial fibrosis was observed at two months of age, prominent collagen deposition was detected by six months in the cortex and medulla of AZGP1-/- mice, persisting through ten months. CONCLUSIONS: These findings identify AZGP1 expressed in proximal tubular cells as protective against kidney fibrosis associated with aging and is a candidate therapeutic target.