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Transcriptional profiling of a mouse model of Uromodulin Associated Kidney Disease (UAKD)

ABSTRACT: Uromodulin (UMOD) is a secreted glycoprotein exclusively expressed by the cells lining the thick ascending limb of the loop of henle and the early distal tubule of the kidney nephron. Mutations in UMOD that interfere with proper folding of the protein are responsible for a progressive form of interstitial fibrotic kidney disease that leads to end stage renal disease, referred to as Uromodulin Associated Kidney Disease (UAKD). To assess key transcriptional changes associated with the progression of UAKD, we generated a knock-in mouse model harboring the mouse equivalent of the human mutation C148W. We profiled both the whole kidney tissue, as well as the specific UMOD+ cell populaitons in mutant and wild type mice. Analysis of differentially expressed genes in whole tissue and UMOD+ cells revealed a strong TNF-signaling signature, as well as TRIB3 upregulation, which is a key mediator of the intrinsic ER-stress mediated cell death pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE102566 | GEO | 2017/09/01

SECONDARY ACCESSION(S): PRJNA398043

REPOSITORIES: GEO

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Project description:Background: Uromodulin (Tamm-Horsfall) protein is secreted by the thick ascending limb into urine and crosses the basolateral membrane into the kidney interstitium and blood. Uromodulin may engage the kidney’s innate immune system with pro and anti-inflammatory effects described. Mutations in the UMOD gene are a cause of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to protein misfolding and endoplasmic reticulum stress. We identified a family with a UMOD mutation (C106F) that leads to glomerular and interstitial inflammation atypical for ADTKD. Methods: To determine if the observed phenotype is due to mutant uromodulin induced changes in the innate or adaptive immune system, we developed a transgenic (tg) mouse with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene using CRISPR-Cas9 gene editing. Results: LLC-PK1 cells expressing wt and mutant protein had increased basolateral secretion of protein compared with cells expressing wt or mutant protein alone. EM examination of mutant medium showed protein aggregates in contrast to filaments in wt medium. Immunoprecipitation of plasma uromodulin from mutant mice demonstrated aggregate formation not seen in wt mice. Tg/+ mice displayed increased F4/80+ mononuclear phagocyte (MP) and podocyte inflammasome activity at baseline. Tg/+ mice developed glomerular and interstitial matrix deposition, myofibroblast proliferation and increased Creatinine with aging. Following ischemia-reperfusion injury, tg/+ mice had no increase in inflammasome activation over baseline in contrast to wt littermates and displayed improved tubular repair and renal function at 7 days. Differential gene expression analysis by RNA sequencing of kidney MP revealed activation of the ATF4 mediated stress response pathway and genes associated with the development of tissue fibrosis. Conclusions: The C106F mutation results in glomerular and interstitial inflammatory kidney disease due to interaction of aggregated misfolded protein with mononuclear phagocytic cells resulting in ER stress response. The resulting alteration in the immune system leads to improved kidney repair following acute injury but fibrosis and chronic renal failure with aging.

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Transcriptional profiling of a mouse model of Uromodulin Associated Kidney Disease (UAKD)

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