Exogenous uromodulin and tubular responses in a model of oxalate-induced kidney injury.

Crystalline nephropathies are associated with kidney injury. Uromodulin (Umod), a glycoprotein produced in the kidneys, regulates salt transport, protecting against urinary tract infections, kidney stones, and kidney injury, contributing to innate immunity. After cleavage by the protease hepsin, Umod is secreted into the tubular lumen. We hypothesize that exogenous Umod may reduce injury associated with crystalline nephropathy. Both in vivo and in vitro models were used. Eight-week-old C57BL/6J male mice were treated with sodium oxalate (NaOx, 9 mg/100 g body wt) and/or Umod (5 µg/animal) and compared with controls. The ST-1 cell line (mouse thick ascending limb of loop of Henle) was treated with calcium oxalate (CaOx; 200 µg/mL) for 6 or 24 h and compared with controls. NaOx treatment caused tubular injury and upregulated proinflammatory and profibrotic factors. Exogenous Umod attenuated NaOx-induced kidney injury. In vitro CaOx treatment decreased Umod expression and induced apoptosis in ST-1 cells, confirmed by elevated caspase-8 immunostaining, whereas Umod reduced the apoptotic response. This study demonstrates that Umod cotreatment attenuated several aspects of NaOx-induced kidney injury. These findings suggest that the multifunctional nature of Umod may have clinical relevance and support the potential utility of urinary Umod as a biomarker of kidney health.NEW & NOTEWORTHY This study sheds light on the potential role of exogenous uromodulin in modulating tubular responses to oxalate-induced kidney injury. By exploring its influence on epithelial stress, inflammation, and protein trafficking, these findings provide a more comprehensive understanding of uromodulin's function beyond its known structural and antimicrobial properties. These insights may inform future strategies for preserving tubular integrity in crystal-related renal disorders.