Caspase-1 inhibition alleviates acute renal injury in rats with severe acute pancreatitis

Abstract

AIM: To assess the effect of inhibition of caspase-1 on acute renal injury in rats with severe acute pancreatitis (SAP).

METHODS: Forty-two Sprague-Dawley rats were randomly divided into three groups: healthy controls (HC, n = 6), SAP rats treated with saline (SAP-S, n = 18), or SAP rats treated with a caspase-1/interleukin (IL)-1β-converting-enzyme (ICE) inhibitor (SAP-I-ICE, n = 18). SAP was induced by retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct. HC rats were subjected to identical treatment and surgical procedures without sodium taurocholate. Rats received an intraperitoneal injection of isotonic saline (SAP-S) or the inhibitor (SAP-ICE-I) at 2 and 12 h after induction of acute pancreatitis. Surviving rats were sacrificed at different time points after SAP induction; all samples were obtained and stored for subsequent analyses. The levels of blood urea nitrogen (BUN) and creatinine (Cr) were measured using automatic methods, and serum IL-1β concentrations were measured by an enzyme-linked immunosorbent assay. Intrarenal expression of IL-1β, IL-18 and caspase-1 mRNAs was detected by RT-PCR. IL-1β protein expression and the pathologic changes in kidney tissues were observed by microscopy after immunohistochemical or hematoxylin and eosin staining, respectively.

RESULTS: The serum levels of BUN and Cr in the SAP-S group were 12.48 ± 2.30 mmol/L and 82.83 ± 13.89 μmol/L at 6 h, 23.53 ± 2.58 mmol/L and 123.67 ± 17.67 μmol/L at 12 h, and 23.60 ± 3.33 mmol/L and 125.33 ± 21.09 μmol/L at 18 h, respectively. All were significantly increased compared to HC rats (P < 0.01 for all). Levels in SAP-ICE-I rats were significantly decreased compared to SAP-S rats both at 12 and 18 h (P < 0.01 for all). Serum IL-1β levels in the SAP-S group were 276.77 ± 44.92 pg/mL at 6 h, 308.99 ± 34.95 pg/mL at 12 h, and 311.60 ± 46.51 pg/mL at 18 h; all significantly higher than those in the HC and SAP-ICE-I groups (P < 0.01 for all). Intrarenal expression of IL-1β mRNA was weak in HC rats, but increased significantly in SAP-S rats (P < 0.01). ICE inhibition significantly decreased the expression of IL-1β and IL-18 mRNAs (P < 0.05 for all vs SAP-S), whereas caspase-1 mRNA expression was not significantly different. Weak IL-1β immunostaining was observed in HC animals, and marked staining was found in the SAP-S group mainly in renal tubular epithelial cells. IL-1β immunostaining was significantly descended in SAP-ICE-I rats compared to SAP-S rats (P < 0.05). Caspase-1 inhibition had no effect on the severity of kidney tissue destruction.

CONCLUSION: The expression of caspase-1-activated cytokines IL-1β and IL-18 plays a pivotal role in acute renal injury in rats with experimental SAP. Caspase-1 inhibition improves renal function effectively.

Keywords: Severe acute pancreatitis, Caspase-1, Interleukin-1β, Interleukin-18, Acute renal injury

Core tip: Activation of caspase-1/interleukin (IL)-1β-converting-enzyme (ICE) and the over-production of IL-18 and IL-1β in the kidney play a pivotal role during the process of acute renal injury in severe acute pancreatitis. Furthermore, ICE inhibitors are effective in improving renal function. The mechanisms of ICE inhibition may be associated with descended cytokine mediated injury and decreased renal cell apoptosis. Therefore, the study of the mechanism of acute renal injury in severe acute pancreatitis may help identify measures for the prevention and treatment, as well as supply novel information to further our understanding of systemic inflammatory response syndrome and multiple system organ failure.