التفاصيل البيبلوغرافية
| العنوان: |
Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease. |
| المؤلفون: |
Schiano, Guglielmo, Lake, Jennifer, Mariniello, Marta, Schaeffer, Céline, Harvent, Marianne, Rampoldi, Luca, Olinger, Eric, Devuyst, Olivier |
| المصدر: |
EMBO Molecular Medicine; 12/7/2023, Vol. 15 Issue 12, p1-21, 21p |
| الملخص (بالإنجليزية): |
Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain‐of‐function mutations, end‐organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated UmodC171Y and UmodR186S knock‐in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild‐type Umod allele in heterozygous UmodR186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation‐specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD‐UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin. [ABSTRACT FROM AUTHOR] |
| Abstract (German): |
Synopsis: Representative missense mutations in the UMOD gene causing ADTKD differentially drive the formation of mutant uromodulin aggregates, impacting on kidney damage and disease progression. Enhancement of autophagy decreased uromodulin aggregates, relevant for therapeutic strategies in ADTKD. Two Umod KI models show strong allelic and gene dosage effects on uromodulin aggregates and activation of inflammation and fibrosis, leading to variable kidney damage.The wild‐type Umod allele protects against the formation of uromodulin aggregates.Studies in kidney tubular cells support mutation‐specific effects on uromodulin aggregates and activation of quality control and clearance mechanisms.Enhancement of autophagy by mTORC1 inhibition decreased uromodulin aggregates. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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