Downregulation of G protein-coupled receptor kinase 4 protects against kidney ischemia-reperfusion injury

Donghai Yang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Ming Tang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Mingming Zhang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Xiaoping Li, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Ziyue Zhang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Bo He, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Song Peng, Department of Urology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Wei Wang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Dandong Fang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yi Song, Department of Cardiac Surgery, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Yao Xiong, Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China.
Zhi Zhao Liu, Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China.
Lijia Liang, Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China.
Weibin Shi, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Chunjiang Fu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yijie Hu, Department of Cardiac Surgery, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Pharmacology-Physiology, The George Washington University School of Medicine & Health Sciences, Washington D.C., USA.
Lin Zhou, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Yu Han, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. Electronic address: hanc2-823@126.com.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, People's Republic of China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China. Electronic address: chunyuzeng01@163.com.

Document Type

Journal Article

Publication Date

1-18-2023

Journal

Kidney international

DOI

10.1016/j.kint.2022.12.023

Keywords

GRK4; STAT1; ischemia and reperfusion injury; nanoparticle; necroptosis

Abstract

Ischemia/reperfusion injury of the kidney is associated with high morbidity and mortality, and treatment of this injury remains a challenge. G protein-coupled receptor kinase 4 (GRK4) plays a vital role in essential hypertension and myocardial infarction, but its function in kidney ischemia/reperfusion injury remains undetermined. Among the GRK subtypes (GRK2-6) expressed in kidneys, the increase in GRK4 expression was much more apparent than that of the other four GRKs 24 hours after injury and was found to accumulate in the nuclei of injured mouse and human kidney tubule cells. Gain- and loss-of-function experiments revealed that GRK4 overexpression exacerbated acute kidney ischemia/reperfusion injury, whereas kidney tubule-specific knockout of GRK4 decreased injury-induced kidney dysfunction. Necroptosis was the major type of tubule cell death mediated by GRK4, because GRK4 significantly increased receptor interacting kinase (RIPK)1 expression and phosphorylation, subsequently leading to RIPK3 and mixed lineage kinase domain-like protein (MLKL) phosphorylation after kidney ischemia/reperfusion injury, but was reversed by necrostatin-1 pretreatment (an RIPK1 inhibitor). Using co-immunoprecipitation, mass spectrometry, and siRNA screening studies, we identified signal transducer and activator of transcription (STAT)1 as a GRK4 binding protein, which co-localized with GRK4 in the nuclei of kidney tubule cells. Additionally, GRK4 phosphorylated STAT1 at serine 727, whose inactive mutation effectively reversed GRK4-mediated RIPK1 activation and tubule cell death. Kidney-targeted GRK4 silencing with nanoparticle delivery considerably ameliorated kidney ischemia/reperfusion injury. Thus, our findings reveal that GRK4 triggers necroptosis and aggravates kidney ischemia/reperfusion injury, and its downregulation may provide a promising therapeutic strategy for kidney protection.

Department

Medicine

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