Diabetic nephropathy (DN) remains a leading cause of end-stage renal failure (ESRD) in the US, presenting an urgent need to develop more sensitive biomarkers and new targets of therapy to halt the progression of DN. Using a microarray profile of a murine model of progressive CKD, we found that the renal expression of Rtn1a positively correlated with the severity of renal injury in animal models, including a model of DN. In addition, expression of RTN1A negatively correlated with estimated glomerular filtration rate (eGFR) in DN patients. Our preliminary data demonstrates that the increased expression of RTN1A, an ER-associated protein, induces ER stress and apoptosis of renal cells and that its reduced expression conversely attenuates tunicamycin-, hyperglycemia-, and albumin-induced ER-stress and apoptosis in vitro. In vivo, a global knockdown of Rtn1a attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ- induced diabetic mice, as well as renal fibrosis in an experimental model of ureteral obstruction. Based on these findings, we posit that RTN1 is a potential novel risk gene for kidney disease and that it promotes the progression of DN through ER stress. In this application we put forward the aims to determine the renal cell- specific role of RTN1A in different stages of DN and the molecular mechanism by which RTN1A induces ER stress and apoptosis under diabetic conditions. The proposed studies herein will confirm whether RTN1A may be developed as a potential drug target to treat DN.

Public Health Relevance

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in the US. However current regimen provides only partial therapeutic effects and the incidence and prevalence of DKD remains high, suggesting that the key pathogenic mechanisms driving DKD progression are not adequately inhibited by current treatments. Therefore, better understanding of mechanisms that mediate the early stage of DKD and drive the disease progression is urgently required to identify novel preventive and therapeutic measures for DKD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK109683-01
Application #
9126016
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2016-04-18
Project End
2020-02-29
Budget Start
2016-04-18
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
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
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
He, Li; Fan, Ying; Xiao, Wenzhen et al. (2017) Febuxostat attenuates ER stress mediated kidney injury in a rat model of hyperuricemic nephropathy. Oncotarget 8:111295-111308
Fan, Ying; Zhang, Jing; Xiao, Wenzhen et al. (2017) Rtn1a-Mediated Endoplasmic Reticulum Stress in Podocyte Injury and Diabetic Nephropathy. Sci Rep 7:323
Fan, Ying; Xiao, Wenzhen; Lee, Kyung et al. (2017) Inhibition of Reticulon-1A-Mediated Endoplasmic Reticulum Stress in Early AKI Attenuates Renal Fibrosis Development. J Am Soc Nephrol 28:2007-2021
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
Zhong, Fang; Mallipattu, Sandeep K; Estrada, Chelsea et al. (2016) Reduced Kr├╝ppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy. Am J Pathol 186:2021-2031
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
Menon, Madhav C; He, John C (2016) Prostaglandin I2 Receptor Agonism for Proteinuria and Diabetes: Good for the Goose and Good for the Gander? Diabetes 65:1149-51