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Volume 25
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10.3390/ijms252312563
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice

by
Kyuho Jeong
1,2,†,
Jihyun Je
1,2,†,
Theodomir Dusabimana
1,
Jacques Karekezi
1,3,
Tatang Aldi Nugroho
1,3,
Edvard Ntambara Ndahigwa
1,3,
Seung Pil Yun
1,3,
Hye Jung Kim
1,3,
Hwajin Kim
1,3,* and
Sang Won Park
1,3,*
1
Department of Pharmacology, Institute of Medical Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea
2
Department of Biochemistry, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
3
Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju 52727, Republic of Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(23), 12563; https://doi.org/10.3390/ijms252312563
Submission received: 17 October 2024 / Revised: 20 November 2024 / Accepted: 21 November 2024 / Published: 22 November 2024
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

Extracellular ATP plays an important role in renal physiology as well as the pathogenesis of acute kidney injury induced by renal ischemia and reperfusion (IR). Expression of the purinergic P2Y2 receptor has been shown on inflammatory and structural cells of the kidney, and P2Y2R is preferably activated by ATP (or UTP). Here, we investigated the molecular mechanism of P2Y2R during IR injury by using P2Y2R knockout (KO) mice and a selective P2Y2R agonist, MRS2768. After renal IR, P2Y2R KO mice showed greater increases in plasma creatinine, tubular damage and neutrophil infiltration, and significant induction of proinflammatory cytokines and apoptotic markers than wild-type (WT) mice. In contrast, treatment with MRS2768 reduced plasma creatinine levels, tubular damage and inflammation, and renal apoptosis in mice subjected to renal IR. In cultured human proximal tubular HK-2 cells, MRS2768 upregulated P2Y2R mRNA levels and decreased TNF-α/cycloheximide-induced apoptosis and inflammation. Importantly, P2Y2R activation by MRS2768 increased the phosphorylation of protein kinase C (PKC), Src, and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, the inhibition of PI3K/Akt abolished the protective effects of MRS2768 against TNF-α/cycloheximide-induced apoptosis and inflammation in HK-2 cells. In conclusion, activation of P2Y2R protects against tubular apoptosis and inflammation during renal IR via the PKC/Src/Akt pathway, suggesting P2Y2R is a promising therapeutic target for acute kidney injury.
Keywords: acute kidney injury; ATP; purinergic P2Y2 receptor; renal ischemia and reperfusion; proximal tubular cells acute kidney injury; ATP; purinergic P2Y2 receptor; renal ischemia and reperfusion; proximal tubular cells

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MDPI and ACS Style

Jeong, K.; Je, J.; Dusabimana, T.; Karekezi, J.; Nugroho, T.A.; Ndahigwa, E.N.; Yun, S.P.; Kim, H.J.; Kim, H.; Park, S.W. Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice. Int. J. Mol. Sci. 2024, 25, 12563. https://doi.org/10.3390/ijms252312563

AMA Style

Jeong K, Je J, Dusabimana T, Karekezi J, Nugroho TA, Ndahigwa EN, Yun SP, Kim HJ, Kim H, Park SW. Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice. International Journal of Molecular Sciences. 2024; 25(23):12563. https://doi.org/10.3390/ijms252312563

Chicago/Turabian Style

Jeong, Kyuho, Jihyun Je, Theodomir Dusabimana, Jacques Karekezi, Tatang Aldi Nugroho, Edvard Ntambara Ndahigwa, Seung Pil Yun, Hye Jung Kim, Hwajin Kim, and Sang Won Park. 2024. "Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice" International Journal of Molecular Sciences 25, no. 23: 12563. https://doi.org/10.3390/ijms252312563

APA Style

Jeong, K., Je, J., Dusabimana, T., Karekezi, J., Nugroho, T. A., Ndahigwa, E. N., Yun, S. P., Kim, H. J., Kim, H., & Park, S. W. (2024). Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice. International Journal of Molecular Sciences, 25(23), 12563. https://doi.org/10.3390/ijms252312563

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