Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease.
Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease.
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DOI：
10.15252/emmm.202318242
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发表时间：
2023-12-07
影响因子：
11.1
通讯作者：
Devuyst, Olivier
中科院分区：
文献类型：
--
作者：
Schiano, Guglielmo;Lake, Jennifer;Mariniello, Marta;Schaeffer, Celine;Harvent, Marianne;Rampoldi, Luca;Olinger, Eric;Devuyst, Olivier
尿调节蛋白（UMOD）基因的错义突变导致常染色体显性遗传性肾小管间质性肾病（ADTKD），这是最常见的单基因肾病之一。等位基因和基因剂量效应的未知影响以及突变型尿调蛋白的命运在ADTKD中假定的功能获得性突变、终末器官损伤和疾病进展之间留下了差距。基于两种普遍的错义UMOD突变与不同的疾病进展，我们产生了Umod C171 Y和Umod R186 S敲入小鼠，其对尿调节蛋白聚集体和ER应激和未折叠蛋白的激活以及免疫应答显示出强烈的等位基因和基因剂量效应，导致可变的肾损伤。在杂合Umod R186 S小鼠中缺失野生型Umod等位基因增加了尿调蛋白聚集体和ER应激的形成。在肾小管细胞中的研究证实了尿调蛋白聚集体的差异，以及突变特异性质量控制和清除机制的激活。通过饥饿和mTORC 1抑制增强自噬减少尿调蛋白聚集体。这些研究证实了毒性聚集体在驱动ADTKD-UMOD进展中的作用，与改善突变型尿调蛋白清除的治疗策略相关。引起ADTKD的UMOD基因中的代表性错义突变差异性地驱动突变型尿调蛋白聚集体的形成，从而影响肾损伤和疾病进展。增强自噬减少尿调蛋白聚集，与ADTKD的治疗策略相关。
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 Umod C171Y and Umod R186S 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 Umod R186S 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. 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.
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影响因子：
7.7
作者：
Brunati M;Perucca S;Han L;Cattaneo A;Consolato F;Andolfo A;Schaeffer C;Olinger E;Peng J;Santambrogio S;Perrier R;Li S;Bokhove M;Bachi A;Hummler E;Devuyst O;Wu Q;Jovine L;Rampoldi L
通讯作者：
Rampoldi L
影响因子：
2.3
作者：
Gast, Christine;Marinaki, Anthony;Venkat-Raman, G.
通讯作者：
Venkat-Raman, G.
DOI：
10.1093/ndt/gfx066
发表时间：
2017-12-01
期刊：
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
影响因子：
--
作者：
Edwards N;Olinger E;Adam J;Kelly M;Schiano G;Ramsbottom SA;Sandford R;Devuyst O;Sayer JA
通讯作者：
Sayer JA
影响因子：
64.8
作者：
Arseni D;Hasegawa M;Murzin AG;Kametani F;Arai M;Yoshida M;Ryskeldi-Falcon B
通讯作者：
Ryskeldi-Falcon B
影响因子：
15.9
作者：
Johnson, Bryce G.;Dang, Lan T.;Duffield, Jeremy S.
通讯作者：
Duffield, Jeremy S.