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Proximal tubular FHL2, a novel downstream target of hypoxia inducible factor 1, is a protector against ischemic acute kidney injury.
Wang, Yan; Kuang, Ziwei; Xing, Xueqi; Qiu, Yumei; Zhang, Jie; Shao, Dandan; Huang, Jiaxin; Dai, Chunsun; He, Weichun.
Afiliación
  • Wang Y; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Kuang Z; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Xing X; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Qiu Y; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Zhang J; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Shao D; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Huang J; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China.
  • Dai C; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China. daichunsun@njmu.edu.
  • He W; Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, 210003, China. heweichun@njmu.edu.cn.
Cell Mol Life Sci ; 81(1): 244, 2024 May 30.
Article en En | MEDLINE | ID: mdl-38814462
ABSTRACT
Four-and-a-half LIM domains protein 2 (FHL2) is an adaptor protein that may interact with hypoxia inducible factor 1α (HIF-1α) or ß-catenin, two pivotal protective signaling in acute kidney injury (AKI). However, little is known about the regulation and function of FHL2 during AKI. We found that FHL2 was induced in renal tubular cells in patients with acute tubular necrosis and mice model of ischemia-reperfusion injury (IRI). In cultured renal proximal tubular cells (PTCs), hypoxia induced FHL2 expression and promoted the binding of HIF-1 to FHL2 promoter. Compared with control littermates, mice with PTC-specific deletion of FHL2 gene displayed worse renal function, more severe morphologic lesion, more tubular cell death and less cell proliferation, accompanying by downregulation of AQP1 and Na, K-ATPase after IRI. Consistently, loss of FHL2 in PTCs restricted activation of HIF-1 and ß-catenin signaling simultaneously, leading to attenuation of glycolysis, upregulation of apoptosis-related proteins and downregulation of proliferation-related proteins during IRI. In vitro, knockdown of FHL2 suppressed hypoxia-induced activation of HIF-1α and ß-catenin signaling pathways. Overexpression of FHL2 induced physical interactions between FHL2 and HIF-1α, ß-catenin, GSK-3ß or p300, and the combination of these interactions favored the stabilization and nuclear translocation of HIF-1α and ß-catenin, enhancing their mediated gene transcription. Collectively, these findings identify FHL2 as a direct downstream target gene of HIF-1 signaling and demonstrate that FHL2 could play a critical role in protecting against ischemic AKI by promoting the activation of HIF-1 and ß-catenin signaling through the interactions with its multiple protein partners.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Factores de Transcripción / Daño por Reperfusión / Beta Catenina / Lesión Renal Aguda / Proteínas con Homeodominio LIM / Túbulos Renales Proximales / Proteínas Musculares Límite: Animals / Humans / Male Idioma: En Revista: Cell Mol Life Sci Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Factores de Transcripción / Daño por Reperfusión / Beta Catenina / Lesión Renal Aguda / Proteínas con Homeodominio LIM / Túbulos Renales Proximales / Proteínas Musculares Límite: Animals / Humans / Male Idioma: En Revista: Cell Mol Life Sci Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: China