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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1)
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Kimmel, Paul
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Augusta University
Schools of Medicine
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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

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