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Updated: May 22, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Cisplatin-induced acute renal failure in mice is mediated by chymase-activated angiotensin-aldosterone system and
Shin Okui1, Hideyuki Yamamoto, Wen Li
1Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8131, Hyogo, Japan.
Abstract:
Mechanism(s) of cisplatin-induced acute renal failure, as manifested by increases in blood urea nitrogen and creatinine, was evaluated in relation to production and activation of endogenous mediator(s) in mice. In interleukin (IL)-18-deficient (IL-18KO) mice, cisplatin failed to induce acute renal failure. Administration of recombinant IL-18 prior to cisplatin restored acute renal failure in IL-18KO mice. Accumulation of cisplatin in the kidney was not different in IL-18KO and wild-type (WT) mice, but, clearance of cisplatin was more rapid in IL-18KO mice than in WT mice. Cisplatin increased serum levels of aldosterone and angiotensin II in WT mice, but only angiotensin II levels in IL-18 KO mice. Administration of IL-18 augmented plasma levels of aldosterone and angiotensin II in WT mice. Eplerenone, an aldosterone receptor blocker, TY-51469, a chymase inhibitor and PD123319, a selective angiotensin II type 2 (AT2) receptor antagonist, but not benazepril, an angiotensin-converting enzyme inhibitor, and candesartan, a selective angiotensin II type 1 (AT1) receptor antagonist improved acute renal failure caused by cisplatin, confirming involvement of IL-18, aldosterone and angiotensin II in cisplatin-induced, chymase-dependent acute renal failure in mice. These results show that IL-18, aldosterone and angiotensin II synergistically act to prolong the accumulation of cisplatin in the kidney, leading to acute renal failure. Combined therapy with inhibitors for chymase and aldosterone receptors or AT2 receptors might reduce acute renal failure induced by cisplatin.
Insights
Interleukin-18 (IL-18) plays a key role in cisplatin-induced acute kidney injury by increasing cisplatin accumulation. Blocking IL-18, aldosterone, or angiotensin II type 2 receptors may prevent kidney damage.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Cisplatin chemotherapy can cause acute kidney injury (AKI).
- The endogenous mediators involved in cisplatin-induced AKI are not fully understood.
- Interleukin-18 (IL-18) is a pro-inflammatory cytokine implicated in various kidney diseases.
Purpose of the Study:
- To elucidate the role of endogenous mediators, specifically IL-18, in cisplatin-induced AKI.
- To investigate the involvement of aldosterone and angiotensin II in this process.
- To identify potential therapeutic targets for preventing cisplatin nephrotoxicity.
Main Methods:
- Comparison of cisplatin-induced AKI in wild-type (WT) and IL-18-deficient (IL-18KO) mice.
- Administration of recombinant IL-18, aldosterone, and angiotensin II antagonists.
- Measurement of kidney function markers (blood urea nitrogen, creatinine), cisplatin accumulation, and serum mediator levels.
- Evaluation of the effects of specific inhibitors (eplerenone, TY-51469, PD123319, benazepril, candesartan).
Main Results:
- Cisplatin failed to induce AKI in IL-18KO mice, and recombinant IL-18 restored AKI.
- Kidney cisplatin accumulation was similar, but clearance was faster in IL-18KO mice.
- Cisplatin increased aldosterone and angiotensin II in WT mice, and angiotensin II in IL-18KO mice.
- Aldosterone receptor blockers, chymase inhibitors, and AT2 receptor antagonists, but not ACE inhibitors or AT1 receptor antagonists, ameliorated cisplatin-induced AKI.
Conclusions:
- IL-18, aldosterone, and angiotensin II synergistically contribute to cisplatin-induced AKI by prolonging cisplatin accumulation in the kidneys.
- Chymase plays a critical role in this pathway.
- Combined inhibition of chymase and aldosterone receptors or AT2 receptors may offer a protective strategy against cisplatin nephrotoxicity.
