title: Caspase-1 inhibition alleviates acute renal injury in rats with severe acute pancreatitis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Xiao-Hua Zhang, Min-Li Li, Bin Wang, Mei-Xia Guo, Ren-Min Zhu, Department of Gastroenterology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Xiao-Hua Zhang, Min-Li Li, Bin Wang, Mei-Xia Guo, Ren-Min Zhu, Department of Gastroenterology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
authors.forename: Min-Li
authors.initials: ML
authors.lastname: Li
authors.affiliation: Xiao-Hua Zhang, Min-Li Li, Bin Wang, Mei-Xia Guo, Ren-Min Zhu, Department of Gastroenterology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Xiao-Hua Zhang, Min-Li Li, Bin Wang, Mei-Xia Guo, Ren-Min Zhu, Department of Gastroenterology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
authors.forename: Mei-Xia
authors.initials: MX
authors.lastname: Guo
authors.affiliation: Xiao-Hua Zhang, Min-Li Li, Bin Wang, Mei-Xia Guo, Ren-Min Zhu, Department of Gastroenterology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
authors.forename: Ren-Min
authors.initials: RM
authors.lastname: Zhu
mesh_terms: D000208:Acute Disease; D058186:Acute Kidney Injury / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001806:Blood Urea Nitrogen; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000494:pharmacology; D012720:Severity of Illness Index; D013656:Taurocholic Acid; D014764:Viral Proteins / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; C000594089:IL1B protein, rat; D020382:Interleukin-18; D053583:Interleukin-1beta; D012333:RNA, Messenger; D015843:Serpins; D014764:Viral Proteins; D013656:Taurocholic Acid; C074641:interleukin-1beta-converting enzyme inhibitor; D003404:Creatinine; D020170:Caspase 1
keywords: Acute renal injury; Caspase-1; Interleukin-18; Interleukin-1β; Severe acute pancreatitis