Uromodulin deficiency alters tubular injury and interstitial inflammation but not fibrosis in experimental obstructive nephropathy.

Human GWAS and Mendelian genetic studies have linked polymorphic variants and mutations in the human uromodulin gene (UMOD) with chronic kidney disease. The primary function of this kidney-specific and secreted protein remains elusive. This study investigated whether UMOD deficiency modified responses to unilateral ureteral obstruction (UUO)-induced kidney injury. Kidneys harvested from groups of wild-type (UMOD+/+) and knockout (UMOD-/-) male mice (n = 7-10 each) were studied on days 7, 14, and 21. Compared to sham kidneys, UMOD protein levels increased 9-13x after UUO and were associated with increased urinary UMOD levels. Kidney KIM-1 protein levels were higher in the UMOD-/- groups at all time-points (4-14x). The UMOD-/- groups also had higher KIM-1 kidney-to-urine relative ratios (5-35x). In vitro studies using KIM-1 expressing 769-P cells showed lower KIM-1 levels in the presence of UMOD protein. Levels of proapoptotic genes and the epithelial cell apoptotic protein marker M30 were significantly lower in the UMOD-/- groups. Both M30 and KIM-1 colocalized with intraluminal UMOD protein deposits. Interstitial inflammation was less intense in the UMOD-/- groups. Renal fibrosis severity (kidney collagen mRNA and protein) was similar in both genotypic groups on days 7, 14, and 21. Our findings suggest a role for UMOD-dependent inhibition of KIM-1 expression and its apoptotic cell scavenging responses during chronic obstruction-associated tubular injury.

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