Protein S protects against podocyte injury in diabetic nephropathy

Fang Zhong, Haibing Chen, Yifan Xie, Evren U. Azeloglu, Chengguo Wei, Weijia Zhang, Zhengzhe Li, Peter Y. Chuang, Belinda Jim, Hong Li, Firas Elmastour, Jalish M. Riyad, Thomas Weber, Hongyu Chen, Yongjun Wang, Aihua Zhang, Weiping Jia, Kyung Lee, John C. He

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear. Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN. Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DNand healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose-induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the highglucose- and TNF-α-induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose andmediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice. Conclusions Our results support a protective role of PS against glomerular injury in DN progression.

Original languageEnglish
Pages (from-to)1397-1410
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Issue number5
StatePublished - May 2018


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