Abstract
Aim:
To study the effect of selective interleukin-1 β-converting enzyme (ICE, caspase-1) inhibitor on ischemic acute renal failure (ARF).
Methods:
Mouse models of ischemic ARF were treated with the specific ICE inhibitor AC-YVAD-CMK. A renal function assay and renal morphological studies were employed to estimate the renal protective effect of AC-YVAD-CMK. The survival rate of mouse models was also analyzed by a time series test. Furthermore, renal ICE activity, mature interleukin-18 (IL-18) protein expression and interferon-α (IFN-α) mRNA expression were also detected by fluorescent enzyme-linked immunosorbent assay (ELISA), ELISA, and semi-quantitative reverse transcription-polymerase chain reaction, respectively.
Results:
The levels of blood urea nitrogen (BUN) and serum creatinine (Scr) increased remarkably in the model controls compared with the sham-operated groups (P<0.01). Typical renal tubular necrosis was found in the model controls. Renal ICE activity, mature IL-18 protein expression, and IFN-γ mRNA expression were also increased significantly in the model controls compared with the sham-operated groups. The levels of BUN and Scr in the AC-YVAD-CMK therapy group were decreased significantly compared with the untreated model controls (P<0.01). Renal tubulointerstitial lesion was also attenuated significantly (P<0.05). AC-YVAD-CMK therapy alleviated the clinical features of ARF, and increased the survival rate (P<0.01). Furthermore, AC-YVAD-CMK therapy also decreased ICE activity, mature IL-18 protein expression, and IFN-γ mRNA expression in renal tissue (P<0.05).
Conclusion:
The selective ICE inhibitor AC-YVAD-CMK can effectively protect the kidney from acute ischemic lesions. This protective effect is associated with decreased renal ICE activity and suppressed IL-18 maturation and IFN-γ mRNA transcription.
Similar content being viewed by others
Article PDF
References
Carmichael P, Carmichael AR . Acute renal failure in the surgical setting. ANZ J Surg 2003; 73: 144–53.
Wiecek A, Nowicki M, Kokot F, Ritz E . Acute failure of the transplanted kidney – pathophysiology, diagnosis and prevention. Ann Transplant 1996; 1: 5–9.
Ysebaert DK, De Greef KE, De Beuf A, Van Rompay AR, Vercauteren S, Persy VP, et al. T cells as mediators in renal ischemia/reperfusion injury. Kidney Int 2004; 66: 491–6.
Bonventre JV, Zuk A . Ischemic acute renal failure: an inflammatory disease? Kidney Int 2004; 66: 480–5.
Friedewald JJ, Rabb H . Inflammatory cells in ischemic acute renal failure. Kidney Int 2004; 66: 486–91.
Burne-Taney MJ, Kofler J, Yokota N, Weisfeldt M, Traystman RJ, Rabb H, et al. Acute renal failure after whole body ischemia is characterized by inflammation and T cell-mediated injury. Am J Physiol Renal Physiol 2003; 285: F87–94.
Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL . Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 2004; 43: 405–14.
Burne MJ, Daniels F, El Ghandour, A, Mauiyyedi S, Colvin RB, O'Donnell MP, et al. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 2001; 108: 1283–90.
Daemen MA, van't Veer, C, Wolfs TG, Buurman WA . Ischemia/reperfusion-induced IFN-gamma up-regulation: involvement of IL-12 and IL-18. J Immunol 1999; 162: 5506–10.
Kitada H, Suitani A, Yamamoto H, Otomo N, Okabe Y, Inoue S, et al. Attenuation of renal ischemia-reperfusion injury by FR 167653 in dogs. Surgery 2002; 131: 654–9.
Melnikov VY, Faubel S, Siegmund B, Lucia MS, Ljubanovic D, Edelstein CL, et al. Neutrophil-independent mechanisms of caspase-1 and IL-18-mediated ischemic acute tubular necrosis in mice. J Clin Invest 2002; 110: 1083–91.
Dinarello CA . Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. Ann NY Acad Sci 1998; 856: 1–11.
Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995; 378: 88–91.
Paller MS, Hoidal JR, Ferris TF . Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 1984; 74: 1156–64.
Denton MD, Chertow GM, Brady HR . ‘Renal-dose’ dopamine for the treatment of acute renal failure: scientific rationale, experimental studies and clinical trials. Kidney Int 1996; 50: 4–14.
Alkhunaizi AM, Schrier RW . Management of acute renal failure: new perspectives. Am J Kidney Dis 1996; 28: 315–28.
Mitaka C, Hirata Y, Habuka K, Narumi Y, Yokoyama K, Makita K, et al. Atrial natriuretic peptide infusion improves ischemic renal failure after suprarenal abdominal aortic cross-clamping in dogs. Crit Care Med 2003; 31: 2205–10.
Chatterjee PK, Patel NS, Cuzzocrea S, Brown PA, Stewart KN, Mota-Filipe H, et al. The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2 ameliorates ischemic acute renal failure. Cardiovasc Res 2004; 61: 630–43.
Tilney NL, Guttmann RD . Effects of initial ischemia/reperfusion injury on the transplant kidney. J Transplant 1997; 64: 945–7.
Kaushal GP, Singh AB, Shah SV . Identification of gene family of caspases in rat kidney and altered expression in ischemia-reperfusion injury. Am J Physiol 1998; 274: 587–95.
Haq M, Norman J, Saba SR, Ramirez G, Rabb H . Role of IL-1 in renal ischemic reperfusion injury. J Am Soc Nephrol 1998; 9: 614–9.
Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, et al. Impaired IL-18 processing protects caspase-1 deficient mice from ischemic acute renal failure. J Clin Invest 2001; 107: 1145–52.
Hedtjarn M, Leverin AL, Eriksson K, Blomgren K, Mallard C, Hagberg H, et al. Interleukin-18 involvement in hypoxic-is-chemic brain injury. J Neurosci 2002; 22: 5910–9.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the Fatal Diseases Prevention and Cure Program of Zhanjiang (2003).
Rights and permissions
About this article
Cite this article
Liu, Hf., Liang, D., Wang, Lm. et al. Effects of specific interleukin-1β-converting enzyme inhibitor on ischemic acute renal failure in murine models. Acta Pharmacol Sin 26, 1345–1351 (2005). https://doi.org/10.1111/j.1745-7254.2005.00200.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2005.00200.x
Keywords
This article is cited by
-
Renal-targeting triptolide-glucosamine conjugate exhibits lower toxicity and superior efficacy in attenuation of ischemia/reperfusion renal injury in rats
Acta Pharmacologica Sinica (2016)
-
Inflammasomes in infection and inflammation
Apoptosis (2009)