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Theranostics 2023; 13(10):3387-3401. doi:10.7150/thno.84308 This issue Cite

Research Paper

Tubular Elabela-APJ axis attenuates ischemia-reperfusion induced acute kidney injury and the following AKI-CKD transition by protecting renal microcirculation

Mingrui Xiong^1#, Hong Chen^1#, Yu Fan², Muchuan Jin², Dong Yang¹, Yuchen Chen¹, Yu Zhang¹, Robert B. Petersen³, Hua Su⁴, Anlin Peng⁵, Congyi Wang⁶, Ling Zheng^2✉, Kun Huang^1✉

1. Tongji School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science & Technology, Wuhan, China, 430030.
2. Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, China, 430072.
3. Foundational Sciences, Central Michigan University College of Medicine, Mt. Pleasant, MI, USA, 48859.
4. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 430030.
5. Department of Pharmacy, The Third Hospital of Wuhan, Tongren Hospital of Wuhan University, Wuhan, China, 430075.
6. The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China, 430030.
^# These authors contribute equally

✉ Corresponding authors: Ling Zheng, Ph.D., College of Life Sciences, Wuhan University, Wuhan, China 430072. Email: lzhengedu.cn. Kun Huang, Ph.D., Tongji School of Pharmacy, Huazhong University of Science & Technology, Wuhan, China, 430030. Email: kunhuangedu.cn. More

Abstract

Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear.

Methods: Renal tubule specific ELA knockout (Apela^Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela^Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination.

Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela^Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela^Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela^Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol.

Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.

Keywords: elabela, APJ, acute kidney injury, AKI-CKD transition, renal microvascular blood flow

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