Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations.
Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations.
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DOI：
10.1038/s41598-017-07804-6
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发表时间：
2017-08-07
影响因子：
4.6
通讯作者：
Rampoldi L
中科院分区：
文献类型：
--
作者：
Trudu M;Schaeffer C;Riba M;Ikehata M;Brambilla P;Messa P;Martinelli-Boneschi F;Rastaldi MP;Rampoldi L
常染色体显性遗传性肾小管间质肾病(ADTKD)是一种非遗传性疾病，可导致进行性肾损害和肾功能衰竭。编码尿调蛋白的UMOD基因突变导致ADTKD-UMOD相关。尿调蛋白是一种GPI锚定蛋白，仅由Henle‘s环粗大上行支的上皮细胞产生。它在蛋白分解后在管腔内释放，代表着生理条件下人体尿液中含量最丰富的蛋白质。我们以前建立并鉴定了一个表达突变的尿调蛋白(TgUmodC147W)的转基因小鼠模型，该模型概括了ATDKD-UMOD的主要特征。虽然一些研究清楚地证明突变的尿调蛋白在内质网中积聚，但导致肾损伤的机制尚不完全清楚。在我们的工作中，我们使用肾脏转录图谱来确定TgUmodC147W小鼠肾脏发病的早期事件。我们的结果显示，在肾脏损伤的任何功能或组织学证据之前，TgUmodC147W幼鼠的炎症和纤维化水平上调，脂代谢下调。我们还表明，促炎信号在纤维化发生之前就已经存在，并且在出生后第一周就已经存在。早期炎症诱导可能与ADTKD-UMOD的发病机制有关，相关途径可被设想为治疗干预的可能新靶点。
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 (TgUmodC147W) 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 TgUmodC147W mice. Our results demonstrate up-regulation of inflammation and fibrosis and down-regulation of lipid metabolism in young TgUmodC147W 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.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
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
DOI：
10.2215/cjn.01220211
发表时间：
2011-10-01
影响因子：
9.8
作者：
Bollee, Guillaume;Dahan, Karin;Knebelmann, Bertrand
通讯作者：
Knebelmann, Bertrand
影响因子：
4
作者：
Hart, TC;Gorry, MC;Bleyer, AJ
通讯作者：
Bleyer, AJ
影响因子：
9.8
作者：
Bolar, Nikhita Ajit;Golzio, Christelle;Loeys, Bart L.
通讯作者：
Loeys, Bart L.