Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease

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• 作者：Ellian Wang¹ ; ² ; Yuan-Yow Chiou³ ; Wen-Yih Jeng⁴ ; ⁵ ; Hsiu-Kuan Lin⁶ ; Hsi-Hui Lin⁶ ; Hsian-Jean Chin² ; Chi-Kuang Leo Wang² ; Shang-Shiuan Yu² ; ⁷ ; Shih-Chieh Tsai² ; Chih-Ying Chiang² ; Po-Hao Cheng² ; Hong-Jie Lin⁴ ; Si-Tse Jiang² ; ⁷ ; ^{stjiang@nlac.org.tw} ; Sou-Tyau Chiu⁸ ; ^{soutyauchiu@yahoo.com.tw} ; Hsiu Mei Hsieh-Li¹ ; ^{hmhsieh@ntnu.edu.tw}
• 关键词：cysts ; neutrophil gelatinase-associated lipocalin ; Pkd1
• 刊名：Kidney International
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：91
• 期：2
• 页码：412-422
• 全文大小：2236 K
• 卷排序：91

文摘

Neutrophil gelatinase-associated lipocalin (Ngal) is a biomarker for acute and chronic renal injuries, including polycystic kidney disease (PKD). However, the effect of Ngal on PKD progression remains unexplored. To study this, we generated 3 strains of mice with different expression levels of Ngal within an established PKD model (Pkd1L3/L3): Pkd1L3/L3 (with endogenous Ngal), Pkd1L3/L3; NgalTg/Tg (with endogenous and overexpression of exogenous kidney-specific Ngal) and Pkd1L3/L3; Ngal-/- mice (with Ngal deficiency). Knockout of endogenous Ngal had no effect on phenotypes, cystic progression, or survival of the PKD mice. However, the transgenic mice had a significantly longer lifespan, smaller (but not fewer) renal cysts, and less interstitial fibrosis than the mice without or with endogenous Ngal. Western-blot analyses showed significant increases in Ngal and cleaved caspase-3 and decreases in α-smooth muscle actin, hypoxia-inducible factor 1-α, pro-caspase 3, proliferating cell nuclear antigen, Akt, mammalian target of rapamycin, and S6 Kinase in the transgenic mice as compared with the other 2 strains of PKD mice. Thus, overexpression of exogenous kidney-specific Ngal reduced cystic progression and prolonged the lifespan in PKD mice, was associated with reductions in interstitial fibrosis and proliferation, and augmented apoptosis.