Abstract
Uromodulin-associated kidney disease (UAKD) is a hereditary progressive renal disease which can lead to renal failure and requires renal replacement therapy. UAKD belongs to the endoplasmic reticulum storage diseases due to maturation defect of mutant uromodulin and its retention in the enlarged endoplasmic reticulum in the cells of the thick ascending limb of Henle's loop (TALH). Dysfunction of TALH represents the key pathogenic mechanism of UAKD causing the clinical symptoms of this disease. However, the molecular alterations underlying UAKD are not well understood. In this study, transcriptome profiling of whole kidneys of two mouse models of UAKD, Umod A227T and Umod C93F, was performed. Genes differentially abundant in UAKD affected kidneys of both Umod mutant lines at different disease stages were identified and verified by RT-qPCR. Additionally, differential protein abundances of SCD1 and ANGPTL7 were validated by immunohistochemistry and Western blot analysis. ANGPTL7 expression was down-regulated in TALH cells of Umod mutant mice which is the site of the mutant uromodulin maturation defect. SCD1 was expressed selectively in the S3 segment of proximal tubule cells, and SCD1 abundance was increased in UAKD affected kidneys. This finding demonstrates that a cross talk between two functionally distinct tubular segments of the kidney, the TALH segment and the S3 segment of proximal tubule, exists.
Highlights
Uromodulin-associated kidney disease (UAKD) is a rare dominant hereditary renal disease caused by amino acid-changing mutations in the uromodulin (UMOD) gene [1,2,3]
Hierarchical cluster analysis of all differentially expressed genes in both mutant lines displayed a similar tendency of transcriptional alteration for about 43% of the genes identified as DEGs in one of both Umod mutant mouse lines but which were only significantly regulated in one of the two lines
Little is known about the molecular alterations in UAKD affected kidneys, except of the induction of unfolded protein response and the recently identified activation of non-canonical NF-kB signaling in cells of the thick ascending limb of Henle’s loop (TALH) segment [11]
Summary
Uromodulin-associated kidney disease (UAKD) is a rare dominant hereditary renal disease caused by amino acid-changing mutations in the uromodulin (UMOD) gene [1,2,3]. UMOD represents the most abundant protein in human urine This glycoprotein was already discovered in the early fifties by Tamm and Horsfall ( initially named Tamm-Horsfall-glycoprotein) [5], the biological function of UMOD is still obscure. In various genome-wide association studies, common allelic UMOD promoter variants were identified to be associated with increased risk for complex trait diseases like chronic kidney disease (CKD), hypertension and kidney stones (reviewed in [3]). These variants of the UMOD promoter lead to increased UMOD expression and secretion which results, by influencing salt reabsorption in the kidney, to increased risk of developing hypertension and CKD [10]
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