Comorbid conditions, such as diabetes, increase the severity of acute kidney injury (AKI) and prevents injured kidneys from recovery, resulting in poor prognosis. However, the mechanism underlying the heightened AKI sensitivity in diabetes is largely unknown. We and others recently verified the AKI sensitivity in diabetes and suggested the involvement of inflammation and p53. In diabetic kidneys, our preliminary studies further demonstrated the inactivation of autophagy, a renoprotective mechanism. Mechanistically, we have identified the down-regulation of ULK1, a key autophagy initiator, as a common feature in diabetic kidneys and high glucose-treated kidney cells. ULK1 down-regulation is not associated with mRNA decrease or proteosomal degradation, suggesting the involvement of novel mechanisms. Bioinformatics analysis suggested the targeting of ULK1 by miR-214, a microRNA induced in diabetic kidneys. Notably, our preliminary data further suggested a role of p53 in miR-214 induction. Based on these findings, we hypothesize that: miR-214 is induced via p53 in diabetes and upon induction, miR-214 represses ULK1 resulting in autophagy impairment, which contributes to AKI sensitivity in diabetes. Specifically, we will determine the role of p53 in miR-214 induction in diabetic kidneys, delineate miR-214 targeting/repression of ULK1, and elucidate autophagy impairment as a key to AKI sensitivity in diabetes. Completion of this project will delineate a novel pathway of p53/miR- 214/ULK1 that leads to autophagy impairment and AKI sensitivity in diabetes. As a result, it may identify miR-214 and autophagy as novel therapeutic targets for AKI therapy and prevention in diabetic patients.

Public Health Relevance

(Relevance) Acute kidney injury (AKI) often associates with co-morbidities, such as diabetes, which worsen AKI and result in poor prognosis. This application will elucidate a novel pathway of p53/miR-214/ULK1 that leads to autophagy impairment in diabetes and heightened AKI sensitivity. As a result, it may identify miR-214 and autophagy as new therapeutic targets for AKI therapy and prevention in diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK058831-15
Application #
9172795
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kimmel, Paul
Project Start
2001-09-01
Project End
2022-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
15
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Augusta University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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