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Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
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Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
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Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
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Journal Article
Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations
2017
Overview
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an inherited disorder that causes progressive kidney damage and renal failure. Mutations in the
UMOD
gene, encoding uromodulin, lead to ADTKD-
UMOD
related. Uromodulin is a GPI-anchored protein exclusively produced by epithelial cells of the thick ascending limb of Henle’s loop. It is released in the tubular lumen after proteolytic cleavage and represents the most abundant protein in human urine in physiological condition. We previously generated and characterized a transgenic mouse model expressing mutant uromodulin (Tg
Umod
C147W
) that recapitulates the main features of ATDKD-
UMOD
. While several studies clearly demonstrated that mutated uromodulin accumulates in endoplasmic reticulum, the mechanisms that lead to renal damage are not fully understood. In our work, we used kidney transcriptional profiling to identify early events of pathogenesis in the kidneys of Tg
Umod
C147W
mice. Our results demonstrate up-regulation of inflammation and fibrosis and down-regulation of lipid metabolism in young Tg
Umod
C147W
mice, before any functional or histological evidence of kidney damage. We also show that pro-inflammatory signals precede fibrosis onset and are already present in the first week after birth. Early induction of inflammation is likely relevant for ADTKD-
UMOD
pathogenesis and related pathways can be envisaged as possible novel targets for therapeutic intervention.
