Acute kidney injury (AKI) induced by renal ischemia-reperfusion continues to be a major kidney disease with unacceptably high mortality rates, increasing prevalence, and no effective therapies. Recent work has further implicated ischemic AKI in the development and progression of chronic kidney diseases. The goal of our research is to delineate the cellular and molecular basis of ischemic AKI and formulate preventive and therapeutic strategies. Using a conditional (renal proximal tubule specific) Dicer- knockout mouse model, we have recently demonstrated the first evidence for the involvement of microRNAs in ischemic AKI. Our microarray analysis has further identified 13 microRNA species that markedly change expression during renal ischemia-reperfusion. Despite these findings, it is unknown which microRNAs contribute significantly to ischemic AKI and how. Our preliminary studies have now verified the dramatic induction of miR-687 early during ischemic AKI. We have further suggested that miR-687 may target PTEN, a key regulator of cell viability, cell cycle, growth, and proliferation. At the upstream level, miR-687 may be subjected to transcriptional regulation by hypoxia-inducible factor, HIF. Based on these findings, we hypothesize that specific microRNA species play important roles in the pathogenesis of ischemic AKI. In these microRNAs, miR-687 is induced via HIF and regulates ischemic AKI by suppressing PTEN and promoting tubular cell survival and regeneration during kidney recovery and repair. We will test this hypothesis by three specific aims: 1) To characterize microRNA expression and determine the roles played by specific microRNAs in ischemic AKI;2) To identify HIF as an upstream transcription factor leading to miR-687 expression during renal ischemia-reperfusion;3) To identify PTEN as a downstream target of miR-687 and a regulator of ischemic AKI. Completion of this project will not only gain novel insights into the molecular regulation of AKI by microRNAs but will also unveil new therapeutic strategies. Targeting microRNAs and their regulatory pathways may lead to clinically applicable approaches for the prevention and treatment of AKI.

Public Health Relevance

Acute kidney injury (AKI) induced by renal ischemia-reperfusion continues to be a major kidney disease with unacceptably high mortality rates (over 50%), increasing prevalence, and no effective therapies. The research of this application will not only unveil a new mechanism of ischemic AKI involving microRNAs and gain insights into the regulation but will also suggest novel therapeutic strategies. Targeting microRNAs and their regulatory pathways may lead to clinically applicable approaches for the prevention and treatment of AKI in the near future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058831-11
Application #
8328629
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2001-02-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$326,250
Indirect Cost
$108,750
Name
Georgia Regents University
Department
Biology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Liu, Jing; Wei, Qingqing; Guo, Chunyuan et al. (2017) Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease. Int J Mol Sci 18:
Guo, Chunyuan; Pei, Lirong; Xiao, Xiao et al. (2017) DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8. Kidney Int 92:1194-1205
Zhang, Dongshan; Pan, Jian; Xiang, Xudong et al. (2017) Protein Kinase C? Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity. J Am Soc Nephrol 28:1131-1144
He, Liyu; Wei, Qingqing; Liu, Jing et al. (2017) AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int 92:1071-1083
Hao, Jielu; Lou, Qiang; Wei, Qingqing et al. (2017) MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-?. J Biol Chem 292:4571-4582
Hao, Jielu; Wei, Qingqing; Mei, Shuqin et al. (2017) Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6. Kidney Int 91:106-118
Yan, Mingjuan; Tang, Chengyuan; Ma, Zhengwei et al. (2016) DNA damage response in nephrotoxic and ischemic kidney injury. Toxicol Appl Pharmacol 313:104-108
Lou, Qiang; Hu, Yanzhong; Ma, Yuanfang et al. (2016) Heat shock factor 1 induces crystallin-?B to protect against cisplatin nephrotoxicity. Am J Physiol Renal Physiol 311:F94-F102
Liu, Zhiwen; Wang, Shixuan; Mi, Qing-Sheng et al. (2016) MicroRNAs in Pathogenesis of Acute Kidney Injury. Nephron 134:149-153
Tang, Chengyuan; Cai, Juan; Dong, Zheng (2016) Mitochondrial dysfunction in obesity-related kidney disease: a novel therapeutic target. Kidney Int 90:930-933

Showing the most recent 10 out of 54 publications