Four-and-a-half LIM domains protein 2 is a coactivator of Wnt signaling in diabetic kidney disease

Szu Yuan Li, Po Hsun Huang*, Der-Cherng Tarng, Tzu Ping Lin, Wu Chang Yang, Yen Hwa Chang, An Hang Yang, Chih Ching Lin, Muh Hwa Yang, Jaw-Wen Chen, Geert W. Schmid-Schönbein, Shu Chien, Pao Hsien Chu, Shing Jong Lin

*此作品的通信作者

研究成果: Article同行評審

27 引文 斯高帕斯(Scopus)

摘要

Diabetic kidney disease (DKD) is amicrovascular complication that leads to kidney dysfunction and ESRD, but the underlyingmechanisms remain unclear. PodocyteWnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/b-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-inducedDKDmodel in FHL2 gene-knockoutmice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-b1, activated FHL2 protein and Wnt/b-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigatedthe podocyte dedifferentiation causedby activatedWnt/b-catenin signalingunderWnt-On, but not underWnt-Off, conditions. Diabetic FHL2+/+ mice developedmarkedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2+/+ mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactionswith b-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigateWnt/b-catenin-induced podocytopathy.

原文English
頁(從 - 到)3072-3084
頁數13
期刊Journal of the American Society of Nephrology
26
發行號12
DOIs
出版狀態Published - 12月 2015

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