Acute kidney injury (AKI) is a major renal disease that is associated with high mortality and prevalence. Recent work further indicates that AKI contributes to the development and progression of chronic kidney disease (CKD). However, the mechanism of AKI-CKD transition is largely unclear. Renal interstitial fibrosis is a key pathological event in maladaptive kidney repair following AKI and its progression to CKD. While interstitial fibrosis may involve various cell types in post-AKI kidneys, the tubular epithelium plays a critical role. It has been suggested that hyperactive signaling in injured or regenerating tubules may enhance the production and release of profibrotic factors that drive downstream events for renal fibrosis and AKI-CKD transition. But, it remains elusive how the profibrotic status of renal tubules is induced and maintained in post-AKI kidneys. Autophagy is a cellular process of cytoplasmic degradation that has recently been implicated in the development of renal fibrosis; however, the published data are controversial and the role of autophagy in post-AKI renal fibrosis is largely unknown. Our preliminary data show that tubular autophagy is induced along with renal interstitial fibrosis weeks after ischemia/reperfusion (IR) AKI. This is associated by the activation of hypoxia-inducible factor 1 (HIF-1), a potential regulator of autophagy and fibrosis. In cultured cells, hypoxia induces the secretion of profibrotic factors in an autophagy-dependent manner. In the model of unilateral ureteral obstruction, blockade of autophagy results in the suppression of renal fibrosis. Based on these observations, we hypothesize that: Autophagy is induced via HIF-1 in renal tubular cells of post-IR kidneys. Upon induction, autophagy leads to a secretory phenotype in these tubular cells for the production and secretion of profibrotic factors, which activate interstitial fibroblasts to promote renal fibrosis. To test this hypothesis, the application will determine the role of tubular autophagy in post-IR renal fibrosis, delineate the involvement of HIF-1 in autophagy activation, and identify the key profibrotic factors that are produced in renal tubules in an autophagy-dependent manner for interstitial fibroblast activation. By elucidating tubular autophagy in post-AKI renal fibrosis, this application may lead to an in-depth understanding of AKI-CKD transition and the discovery of new therapeutic strategies.

Public Health Relevance

In the United States, over 300,000 cases of acute kidney injury (AKI) are diagnosed each year with high mortality and staggering medical expense. Veterans are highly susceptible to AKI as shown by the Austin Automation Center Patient Files. AKI is also a common complication among military casualties in battle-fields. Moreover, AKI is an important factor for the development and progression of chronic kidney disease (CKD) that contributes significantly to cardiovascular disease and mortality in aging patients including veterans. In the general population, 15-20% of AKI cases progress to CKD within 24 months; however, AKI-CKD transition in veterans is markedly higher and faster, reaching 31.8% in 12 months (Heung et al. Am J Kidney Dis 2016, 67:742-52). By elucidating autophagy in AKI-CKD transition, this application may lead to novel strategies for the prevention and treatment of this devastating disease, contributing significantly to the improvement of veterans? health.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Nephrology (NEPH)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Charlie Norwood VA Medical Center
United States
Zip Code
Yang, Danyi; Livingston, Man J; Liu, Zhiwen et al. (2018) Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell Mol Life Sci 75:669-688
Wang, Shixuan; Liu, Aimin; Wu, Guangyu et al. (2018) The CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation. Nat Commun 9:1234
Liu, Jing; Wei, Qingqing; Guo, Chunyuan et al. (2017) Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease. Int J Mol Sci 18:
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
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
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
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
Wang, Shixuan; Dong, Zheng (2016) Environmental hit on a genetic basis in polycystic kidney disease. Am J Physiol Renal Physiol 311:F1358-F1359
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

Showing the most recent 10 out of 41 publications