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 weight) and/or Umod (5 μg/animal) and compared to controls. The ST-1cell line (mouse thick ascending limb of loop of Henle) was treated with CaOx (200 μg/mL) for 6 or 24 hours and compared with controls. NaOx treatment caused tubular injury and upregulated pro-inflammatory and pro-fibrotic 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, while Umod reduced the apoptotic response. This study demonstrates that Umod co-treatment 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.