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Published on: May 15, 2021
Inhibition of P2Y2 Attenuates Cisplatin-Induced AKI via Reduced Oxidative Stress, Inflammation and Cell Death
Fengyu Su1,2, Ting Wang1,2, Xiuli Lin1,2
1Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Introduction:
Purinergic signaling has been recognized as important extracellular regulator in multiple physiological and pathophysiological conditions. Adenosine triphosphate-purinergic receptor P2Y2 signaling pathway is associated with glomerular nephritis (GN), diabetic nephropathy (DN), and chronic kidney disease. Recently, there has been evidence that global knockout of P2Y2 exacerbated bilateral ischemic reperfusion-induced acute kidney injury (AKI). However, its role in cisplatin-induced AKI (CIA) remains unknown. Cisplatin is a platinum-containing antineoplastic drug widely used in variety of solid malignant tumors. Nephrotoxicity is one of the major serious side effect that limit its clinical use. In the present study, we investigated whether inhibition of P2Y2 has an effect on CIA.
Methods:
We used AR-C118925 (AR-C), a selective antagonist of P2Y2, and gene transfection for interruption of the P2Y2 pathway. Mice were pretreated with AR-C (10 mg/kg/day) and then challenged with cisplatin at a dose of 20 mg/kg. Seventy-two hours after cisplatin administration, all mice developed kidney failure. Knockdown and overexpression of P2Y2 in mice and mouse proximal tubular cells (mPTCs) were employed to validate that ARC acts through P2Y2 receptor.
Results:
AR-C markedly ameliorated cisplatin-induced nephrotoxicity evidenced by improved renal function, renal morphology, and tubular injury marker expression. Further analysis of the mechanism revealed that AR-C significantly reduced kidney oxidative stress, inflammation, apoptosis, and necroptosis. Consistently, AR-C protects mPTCs from injury caused by cisplatin. To verify that AR-C acts through the P2Y2 receptor, we knocked down P2Y2 in mice or in mPTC cells. Both showed beneficial effects, while overexpression of P2Y2 promotes cisplatin-induced cell death.
Conclusion:
Taken together, our study, for the first time revealed that P2Y2 plays an important role in CIA by regulating oxidative stress, inflammation, apoptosis, and necroptosis and its inhibitor, AR-C, is a potential drug for treating CIA.
Insights
Inhibition of P2Y2 receptor signaling with AR-C118925 (AR-C) protects against cisplatin-induced acute kidney injury (AKI). This study demonstrates AR-C
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Purinergic signaling, particularly adenosine triphosphate-purinergic receptor P2Y2, is implicated in kidney diseases like glomerular nephritis and diabetic nephropathy.
- While P2Y2 knockout exacerbates ischemic AKI, its role in cisplatin-induced AKI (CIA) is unknown.
- Cisplatin, a vital chemotherapy drug, causes nephrotoxicity, limiting its clinical application.
Purpose of the Study:
- To investigate the role of P2Y2 signaling in cisplatin-induced AKI (CIA).
- To evaluate the therapeutic potential of P2Y2 inhibition using AR-C118925 (AR-C) against CIA.
Main Methods:
- Mice were pretreated with the selective P2Y2 antagonist AR-C and then challenged with cisplatin.
- Gene transfection was used to manipulate P2Y2 expression in mice and mouse proximal tubular cells (mPTCs).
- Renal function, morphology, oxidative stress, inflammation, apoptosis, and necroptosis markers were assessed.
Main Results:
- AR-C treatment significantly ameliorated cisplatin-induced nephrotoxicity, improving renal function and morphology.
- AR-C reduced kidney oxidative stress, inflammation, apoptosis, and necroptosis.
- P2Y2 knockdown conferred protection, while P2Y2 overexpression exacerbated cisplatin-induced cell death in mPTCs.
Conclusions:
- P2Y2 signaling plays a critical role in the pathogenesis of cisplatin-induced AKI.
- Inhibiting P2Y2 with AR-C demonstrates potential as a therapeutic strategy for CIA.
- AR-C mitigates CIA by modulating oxidative stress, inflammation, and cell death pathways.
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