Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice
Abstract Chronic kidney disease is defined as a progressive loss of kidney function associated with impaired recovery after acute kidney injury. Renal ischemia-reperfusion (IR) induces oxidative stress and inflammatory responses leading to severe tissue damage, where incomplete or maladaptive repair...
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Nature Portfolio
2024-12-01
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| Online Access: | https://doi.org/10.1038/s41598-024-83411-6 |
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| author | Kyuho Jeong Jihyun Je Theodomir Dusabimana Jacques Karekezi Tatang Aldi Nugroho Edvard Ntambara Ndahigwa Hyun Joon Kim Seung Pil Yun Hye Jung Kim Hwajin Kim Sang Won Park |
| author_facet | Kyuho Jeong Jihyun Je Theodomir Dusabimana Jacques Karekezi Tatang Aldi Nugroho Edvard Ntambara Ndahigwa Hyun Joon Kim Seung Pil Yun Hye Jung Kim Hwajin Kim Sang Won Park |
| author_sort | Kyuho Jeong |
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| description | Abstract Chronic kidney disease is defined as a progressive loss of kidney function associated with impaired recovery after acute kidney injury. Renal ischemia-reperfusion (IR) induces oxidative stress and inflammatory responses leading to severe tissue damage, where incomplete or maladaptive repair accelerates renal fibrosis and aging. To investigate the role of the purinergic P2Y2 receptor (P2Y2R) in these processes, we used P2Y2R knockout (KO) mice subjected to IR. KO mice showed severe kidney dysfunction and structural damage compared to WT mice. KO mice showed higher senescence-associated β-galactosidase expression and shorter telomere length than WT mice. Consistently, interstitial collagen accumulation and fibrogenic mediators were significantly upregulated in KO mice. Renal apoptosis and inflammation were highly elevated in KO mice. Interestingly, cell proliferation as shown by Ki-67 and PCNA expression, was increased for 3 days after IR in WT mice, whereas it maintained increased for 14 days in KO mice. Cell cycle inhibitors, p16 and p21, and regulators JunB and cyclin E were significantly increased after IR in KO mice, suggesting that cell cycle progression was impaired during recovery after IR. Proximal tubular cells treated with JunB siRNA showed a reduced expression of fibrogenic mediators and proinflammatory cytokines, consistent with the mice treated with MRS2768, a P2Y2 agonist that downregulated JunB levels. In conclusion, P2Y2R reduces kidney tissue damage after IR and repairs the tissue properly by regulating JunB-mediated signaling during the recovery process. |
| format | Article |
| id | doaj-art-2a182631b131434aa86651c53c9430a4 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-2a182631b131434aa86651c53c9430a42025-01-05T12:25:05ZengNature PortfolioScientific Reports2045-23222024-12-0114111410.1038/s41598-024-83411-6Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in miceKyuho Jeong0Jihyun Je1Theodomir Dusabimana2Jacques Karekezi3Tatang Aldi Nugroho4Edvard Ntambara Ndahigwa5Hyun Joon Kim6Seung Pil Yun7Hye Jung Kim8Hwajin Kim9Sang Won Park10Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Anatomy, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of MedicineAbstract Chronic kidney disease is defined as a progressive loss of kidney function associated with impaired recovery after acute kidney injury. Renal ischemia-reperfusion (IR) induces oxidative stress and inflammatory responses leading to severe tissue damage, where incomplete or maladaptive repair accelerates renal fibrosis and aging. To investigate the role of the purinergic P2Y2 receptor (P2Y2R) in these processes, we used P2Y2R knockout (KO) mice subjected to IR. KO mice showed severe kidney dysfunction and structural damage compared to WT mice. KO mice showed higher senescence-associated β-galactosidase expression and shorter telomere length than WT mice. Consistently, interstitial collagen accumulation and fibrogenic mediators were significantly upregulated in KO mice. Renal apoptosis and inflammation were highly elevated in KO mice. Interestingly, cell proliferation as shown by Ki-67 and PCNA expression, was increased for 3 days after IR in WT mice, whereas it maintained increased for 14 days in KO mice. Cell cycle inhibitors, p16 and p21, and regulators JunB and cyclin E were significantly increased after IR in KO mice, suggesting that cell cycle progression was impaired during recovery after IR. Proximal tubular cells treated with JunB siRNA showed a reduced expression of fibrogenic mediators and proinflammatory cytokines, consistent with the mice treated with MRS2768, a P2Y2 agonist that downregulated JunB levels. In conclusion, P2Y2R reduces kidney tissue damage after IR and repairs the tissue properly by regulating JunB-mediated signaling during the recovery process.https://doi.org/10.1038/s41598-024-83411-6AgingApoptosisCell cycleFibrosisRenal ischemia-reperfusion injuryP2Y2 receptor |
| spellingShingle | Kyuho Jeong Jihyun Je Theodomir Dusabimana Jacques Karekezi Tatang Aldi Nugroho Edvard Ntambara Ndahigwa Hyun Joon Kim Seung Pil Yun Hye Jung Kim Hwajin Kim Sang Won Park Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice Scientific Reports Aging Apoptosis Cell cycle Fibrosis Renal ischemia-reperfusion injury P2Y2 receptor |
| title | Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice |
| title_full | Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice |
| title_fullStr | Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice |
| title_full_unstemmed | Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice |
| title_short | Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice |
| title_sort | deficiency of purinergic p2y2 receptor impairs the recovery after renal ischemia reperfusion injury and accelerates renal fibrosis and tubular senescence in mice |
| topic | Aging Apoptosis Cell cycle Fibrosis Renal ischemia-reperfusion injury P2Y2 receptor |
| url | https://doi.org/10.1038/s41598-024-83411-6 |
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