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

Abstract

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.

Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

“…We postulate that in neonatal UUO pUMOD reaches extratubular renal tissue and induces recruitment of innate immune cells and interstitial inflammation in the neonatal kidney with obstruction. Our findings are in line with observations showing that UMOD protein levels increased in kidneys of adult mice following UUO and uromodulin-deficiency reduced inflammation and kidney injury in this model ( 28 ). Interestingly, interstitial UMOD deposition could not be detected in substantial quantities within Umod +/+ mice with UUO in their study.…”

“…that UMOD protein levels increased in kidneys of adult mice following UUO and uromodulin-deficiency reduced inflammation and kidney injury in this model (28). Interestingly, interstitial UMOD deposition could not be detected in substantial quantities within Umod +/+ mice with UUO in their study.…”

“…In patients with multiple myeloma, pUMOD co-precipitates with monoclonal immunoglobulin free light chains and forms casts which block urinary flow and cause tubular atrophy resulting in progressive interstitial inflammation and fibrosis ( 27 ). Finally, in mouse models of unilateral ureteral obstruction (UUO) accompanied with an inflammatory response, pUMOD accumulation, and extratubular deposition have been documented ( 28 – 30 ). These findings imply a potential proinflammatory role of pUMOD under pathological conditions.…”

Extratubular polymerized uromodulin induces leukocyte recruitment and inflammationin vivo

“…We postulate that in neonatal UUO pUMOD reaches extratubular renal tissue and induces recruitment of innate immune cells and interstitial inflammation in the neonatal kidney with obstruction. Our findings are in line with observations showing that UMOD protein levels increased in kidneys of adult mice following UUO and uromodulin-deficiency reduced inflammation and kidney injury in this model(26). Interestingly, interstitial UMOD deposition could not be detected in substantial quantities within Umod +/+ mice with UUO in their study.…”

“…In patients with multiple myeloma, pUMOD co-precipitates with monoclonal immunoglobulin free light chains and forms casts which block urinary flow and cause tubular atrophy resulting in progressive interstitial inflammation and fibrosis (25). Finally, in mouse models of unilateral ureteral obstruction (UUO) accompanied with an inflammatory response, pUMOD accumulation and extratubular deposition has been documented (26,27). These findings imply a potential proinflammatory role of pUMOD under pathological conditions.…”