Kidney fibrosis is a common final pathway of chronic kidney disease (CKD) leading to end- stage renal failure (ESRD) and specific anti-fibrosis therapy is lacking. Therefore, there is an urgent need to develop effective anti-fibrosis therapy t prevent the progression of CKD. It is known that the kidney fibrosis process is regulated by a complex cell signaling network. The drugs targeting these signaling pathways are of great interest. However, only a few drugs are in early phase of clinical trials. From the systems point of view, kidney fibrosis has a complex pathogenesis and drugs targeting individual signaling pathways may not have sufficient anti-fibrosis effects to prevent the progression of CKD. Therefore, it is important to perform systems analysis of the signaling network. During the last funding period we developed a combined systems biology and experimental approach allowing us to deduce upstream signaling networks from genome-wide gene expression profiles. Using this approach, we identified HIPK2 as a key regulator of genes altered in the kidney of animal model with kidney fibrosis. Furthermore, we confirmed that HIPK2 expression is increased in kidney biopsies from patients with various kidney disease associated with kidney fibrosis. In vitro, we found that HIPK2 mediates injury and activation of pro-fibrosis markers in kidney cells. HIPK2 activates multiple pro-fibrosis and pro-inflammatory signaling pathways leading to kidney fibrosis and inflammation. The role of HIPK2 in kidney fibrosis was also confirmed in mice with HIPK2 deficiency. Our findings indicate that HIPK2 is a key protein kinase mediating kidney fibrosis and suggests that it may be a potential drug target for anti-fibrosis therapy. In this competitive renewal application, we propose to further validate HIPK2 as a drug target for anti-fibrosis therapy and develop specific inhibitors of HIPK2 as anti-fibrosis drugs. These questions will be addressed in the following three specific aims:
Specific aim 1 : We will determine whether conditional knockout of HIPK2 in kidney cells attenuates kidney fibrosis in the animal models of kidney fibrosis. We will also determine whether the induction of HIPK2 expression in kidney cells accelerates renal fibrosis in these animals.
Specific aim 2 : We will determine the cellular and molecular mechanisms by which HIPK2 causes kidney fibrosis.
Specific aim 3 : We will identify specific and potent HIPK2 inhibitors and validate the effects of these inhibitors in cultured kidney cells and animal models of kidney fibrosis.

Public Health Relevance

Renal fibrosis is a common pathway mediating the progression of chronic kidney disease to end stage renal failure. Currently, we don't have any effective therapy for renal fibrosis. Therefore, the proposed studies to identify potential new target and drugs for treatment of renal fibrosis will have enormous clinical value.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088541-10
Application #
9720878
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Maric-Bilkan, Christine
Project Start
2010-04-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2021-06-30
Support Year
10
Fiscal Year
2019
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
Zhong, Fang; Chen, Zhaohong; Zhang, Liwen et al. (2018) Tyro3 is a podocyte protective factor in glomerular disease. JCI Insight 3:
Zhong, Yifei; Lee, Kyung; He, John Cijiang (2018) SIRT1 Is a Potential Drug Target for Treatment of Diabetic Kidney Disease. Front Endocrinol (Lausanne) 9:624
Zhong, Fang; Chen, Haibing; Xie, Yifan et al. (2018) Protein S Protects against Podocyte Injury in Diabetic Nephropathy. J Am Soc Nephrol 29:1397-1410
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
Gu, Xiangchen; Mallipattu, Sandeep K; Guo, Yiqing et al. (2017) The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis. Kidney Int 92:1178-1193
Wei, Chengguo; Li, Li; Menon, Madhav C et al. (2017) Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis. J Am Soc Nephrol 28:1385-1393
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

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