Diabetic kidney disease (DKD) is the common cause of kidney failure. Elucidating mechanisms that mediate the early stage of DKD may help to identify novel preventive and therapeutic measures for patients with DKD. In the previous funding period, we demonstrated a critical role of NF-?B and STAT3 acetylation in DKD through the regulation of inflammatory gene expression (see progress report). To further understand the mechanism of early DKD injury, we performed proteomic studies in the glomeruli of streptozotocin (STZ)-induced diabetic rats and identified protein S (PS) as one of the proteins which were highly regulated in early DKD. PS, coded by Pros1, is a cofactor for the formation of activated protein C (APC). APC formation has been shown to protect glomerular cells from apoptosis in DKD. In addition, PS shares structural similarities with GAS6, which is known to be involved in the pathogenesis of kidney disease. Both PS and GAS6 bind to TAM receptors (Tyro3, Axl, and Mer), which belong to a family of receptor tyrosine kinases that mediates regulation of inflammation as well as cell survival and migration. However, PS and GAS6 have different binding affinity to individual TAM receptors and appear to have different functions. The role of PS and TAM receptors in kidney disease is not known. Our preliminary data suggest that PS expression increased in the glomeruli of diabetic rats and in human kidneys with early DKD, but decreased in those with advanced DKD. Plasma concentrations of PS were not different between diabetic and non-diabetic rats or humans, suggesting a local regulation of PS expression. We found that knockdown of PS in podocytes enhanced high glucose-induced apoptosis while overexpression of PS inhibited TNF-?-induced pro-inflammatory gene expression, suggesting a protective role of PS against diabetes-induced podocyte injury. We found that Tyro3, one of the TMA receptors, was upregulated by high glucose and knockdown of Tyro3 expression abolished the protective effects of PS in podocytes. Tyro3 expression is also upregulated in human glomeruli at early DKD but downregulated at late DKD. We developed podocyte-specific Pros1 knockout mice (KO) and found that diabetic KO mice developed more proteinuria, mesangial expansion, and foot process effacement than diabetic wild-type mice. Based on these findings, we hypothesize that PS may protect glomerular cell injury in early DKD through the formation of APC and/or effects mediated by Tyro3. We will test our hypothesis by two aims: In the aim 1, we will determine the factors which upregulate PS and Tyro3 at early DKD and those suppress PS and Tyro3 at late DKD and the effects of PS and Tyro3 in podocytes cultured in diabetic condition. In the aim 2 we will determine the role of PS and Tyro3 in DKD progression in vivo using both conditional overexpression and knockout mouse models for PS and Tyro3. We believe that the proposed studies could help us to elucidate the mechanism of glomerular cell injury in early DKD and therefore we could develop more effective drugs to prevent the progression of DKD.

Public Health Relevance

Potential Impact on Veterans health Care: Many Veterans suffer from diabetes and diabetic complications including diabetic kidney disease (DKD). DKD is the leading cause of End-stage renal failure (ESRD) in our Veterans patient population. The Veterans on chronic dialysis have a high rate of mobility and mortality and poor quality of life. Dialysis also adds additional emotional burden for our Veterans who have been already suffering from PTSD and other pschychological disorders such as major depression. Therefore, the research to identify the better treatment regimes for patients with DKD will help to reduce the incidence of ESRD in our Veterans and will have enormous impact on Veterans health care. We believe that our study will provide a new approach for the treatment of patients with DKD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000345-09
Application #
9378374
Study Section
Nephrology (NEPH)
Project Start
2009-04-01
Project End
2020-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
James J Peters VA Medical Center
Department
Type
DUNS #
040077133
City
Bronx
State
NY
Country
United States
Zip Code
10468
Liu, Ruijie; Das, Bhaskar; Xiao, Wenzhen et al. (2017) A Novel Inhibitor of Homeodomain Interacting Protein Kinase 2 Mitigates Kidney Fibrosis through Inhibition of the TGF-?1/Smad3 Pathway. J Am Soc Nephrol 28:2133-2143
Dai, Yan; Chen, Anqun; Liu, Ruijie et al. (2017) Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor ?. Kidney Int 92:1444-1457
Fu, Jia; Wei, Chengguo; Lee, Kyung et al. (2016) Comparison of Glomerular and Podocyte mRNA Profiles in Streptozotocin-Induced Diabetes. J Am Soc Nephrol 27:1006-14
Mallipattu, Sandeep K; He, John C (2015) KLF 6: a mitochondrial regulator in the kidney. Oncotarget 6:15720-1
Fan, Ying; Xiao, Wenzhen; Li, Zhengzhe et al. (2015) RTN1 mediates progression of kidney disease by inducing ER stress. Nat Commun 6:7841
Fan, Ying; Li, Xuezhu; Xiao, Wenzhen et al. (2015) BAMBI elimination enhances alternative TGF-? signaling and glomerular dysfunction in diabetic mice. Diabetes 64:2220-33
Zhong, Fang; Chen, Habing; Wei, Chengguo et al. (2015) Reduced Kr├╝ppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy. Kidney Int 87:382-95
Mallipattu, Sandeep K; He, John Cijiang (2015) The beneficial role of retinoids in glomerular disease. Front Med (Lausanne) 2:16
Mallipattu, Sandeep K; Gallagher, Emily J; LeRoith, Derek et al. (2014) Diabetic nephropathy in a nonobese mouse model of type 2 diabetes mellitus. Am J Physiol Renal Physiol 306:F1008-17
Liu, Ruijie; Zhong, Yifei; Li, Xuezhu et al. (2014) Role of transcription factor acetylation in diabetic kidney disease. Diabetes 63:2440-53

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