title: Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage.
abstract: BACKGROUND
  Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure.
  
  
  METHODS
  Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested.
  
  
  RESULTS
  Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67% mortality in vehicle-treated rats, but only 20% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case).
  
  
  CONCLUSIONS
  The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.
authors: Institute for Nutritional Science, University of Potsdam, Germany.
authors: Yuliya
authors: Y
authors: Sharkovska
authors: Philipp
authors: P
authors: Kalk
authors: Karoline
authors: K
authors: von Websky
authors: Katharina
authors: K
authors: Relle
authors: Thiemo
authors: T
authors: Pfab
authors: Markus
authors: M
authors: Alter
authors: Yvan
authors: Y
authors: Fischer
authors: Berthold
authors: B
authors: Hocher
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D003250:Constriction; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology; D006973:Hypertension / Q000139:chemically induced / Q000150:complications; D007668:Kidney / Q000098:blood supply; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009392:Nephrectomy; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; D019331:NG-Nitroarginine Methyl Ester