Diabetic kidney disease is a major public health issue affecting more than 200,000 U.S. individuals with end-stage renal disease, which requires chronic hemodialysis or kidney transplantation to avoid significant morbidity and mortality. Even with the best multi- faceted approach to diabetes management the progression of diabetic nephropathy is only slowed, but not stopped. To develop more effective therapies for this disease we need to have a better understanding of the disease pathogenesis. We recently found that the expression of a protein called sirtuin (SIRT1), which is known to modify and regulate the cell's transcription machinery, is reduced in a rodent model of diabetes as well as human with diabetic nephropathy. Here, we present additional data to support that reduction of SIRT1 increases the susceptibility of mice to kidney injury. We hypothesize that reduction of SIRT1 in the diabetic condition predisposes podocytes to injury. To test our hypothesis we have generated a novel mouse model that allows us to reversibly manipulate SIRT1 expression with both temporal and tissue specificity. With this model we propose to exam the functional role of SIRT1 in the kidney podocyte by studying the development of diabetic kidney disease and podocyte injury in mice with reduced SIRT1 expression. We also aim to identify the molecular mechanism through which SIRT1 reduction causes kidney injury in diabetes. Our results could provide a better understanding of the molecular mechanism of podocyte and kidney injury in diabetes and a novel target of treatment for a disease where currently available therapy is less than optimal.

Public Health Relevance

Diabetic kidney disease is a major public health issue in the US. Even with the best multi-faceted approach to diabetes management the progression of diabetic nephropathy is only slowed, but not stopped. To develop more effective therapies for this disease we need to have a better understanding of the pathogenesis of diabetic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK098126-03
Application #
9122421
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2014-09-20
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
$339,000
Indirect Cost
$139,000
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Hong, Quan; Zhang, Lu; Das, Bhaskar et al. (2018) Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int 93:1330-1343
Fu, Jia; Wei, Chengguo; Zhang, Weijia et al. (2018) Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice. Kidney Int 94:326-345
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
Chuang, Peter Y; Cai, Weijing; Li, Xuezhu et al. (2017) Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. Am J Physiol Renal Physiol 313:F621-F628
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
Xiao, Wenzhen; Fan, Ying; Wang, Niansong et al. (2016) Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload-induced nephropathy. Am J Physiol Renal Physiol 310:F409-15
Mallipattu, Sandeep K; Horne, Sylvia J; D'Agati, Vivette et al. (2015) Krüppel-like factor 6 regulates mitochondrial function in the kidney. J Clin Invest 125:1347-61
Menon, Madhav C; Chuang, Peter Y; Li, Zhengzhe et al. (2015) Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis. J Clin Invest 125:208-21
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

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