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作者:  来源:   发布时间:2014-10-19 04:42:00  浏览次数:

Progranulin protects against renal ischemia/reperfusion injury in mice

 

Meng Zhou1#, Wei Tang2#, Yi Fu1, Xiaoying Xu2, Ziying Wang1, Yi Lu3, Feng Liu3, Xinying Yang4,  Xinbing Wei1, Yan Zhang1, Juan Liu2, Xue Geng1, Chun Zhang5, Qiang Wan6, Ningjun Li7, and Fan Yi1,8*

 

1Department of Pharmacology, Shandong University School of Medicine, Jinan, 250012, China

2Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, 250012, China

3Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, 250012, China

4Institute of Pharmaceutical Analysis, School of Pharmacy, Shandong University, Jinan, 250012, China 

5Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

6Department of Nephrology, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China

7Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA

8Institute of Nephrology, Shandong University, Jinan, 250012, China

#Co-first authors, equally contributes to this work.

 

Running title: PGRN and ischemic renal injury

Words: 3129

 

*Send Correspondence and Reprint Requests to:

 

Fan Yi, Ph.D

Professor

Department of Pharmacology

Shandong University School of Medicine

44#, Wenhua Xi Road,

Jinan, Shandong, 250012, P.R. China

Phone: 86-0531-88382616

Fax:  86-0531-88382616

E-mail: fanyi@sdu.edu.cn




Abstract

 

Progranulin (PGRN), an autocrine growth factor, has multiple physiological functions and is widely involved in the pathogenesis of many types of diseases. The pivotal anti-inflammatory function of PGRN in rheumatoid arthritis encourages us to further elucidate the role of PGRN in acute kidney injury (AKI). In this study, we found that the levels of PGRN were significantly reduced in the kidney from a mouse model of renal ischemia/reperfusion injury (IRI). We further observed that PGRN deficient (Grn-/-) mice significantly aggravated renal injury as evidenced by higher serum creatinine, more severe morphological injury, increased tubular epithelial cell apoptosis, and tubulointerstitial neutrophil and macrophage infiltration versus wild type (WT) mice. In vitro, we demonstrated that recombinant PGRN (rPGRN) attenuated hypoxia-induced inflammatory actions and apoptosis in proximal tubule epithelial cells, which was associated with, at least in part, nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated immune response. Importantly, both WT and Grn-/- mice pretreated with or delayed administration of rPGRN protected against or promoted recovery from renal IRI. Similar renal protective effects were also observed in cisplatin-induced AKI. Collectively, these findings provide new evidence for a better understanding of the biological activities of PGRN in the kidney and suggest that PGRN may be an innovative therapeutic strategy for treating patients with AKI.

 

Key words:

progranulin; acute kidney injury; pattern-recognition receptors; hypoxia; inflammation

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