Influence of the renin-angiotensin system on epidermal growth factor expression in normal and cyclosporine-treated rat kidney

Kidney Int. 2001 Sep;60(3):847-57. doi: 10.1046/j.1523-1755.2001.060003847.x.


Background: Epidermal growth factor (EGF) plays an important role in renal tubular regeneration after ischemic injury in kidney. The present study reports the association between the renin-angiotensin system (RAS) and EGF, and the effect of angiotensin II blockade with losartan (LSRT) on EGF expression in an experimental model of chronic cyclosporine (CsA) nephrotoxicity in rats.

Methods: Two separate experiments were performed. In the first experiment, rats on the normal-salt diet (NSD; 0.3%) or low-salt diet (LSD; 0.05%) were treated with or without LSRT for four weeks. In the second experiment, rats on the NSD or LSD were given vehicle (VH group, olive oil, 1 mg/kg per day) or CsA (15 mg/kg per day) or CsA (15 mg/kg per day) plus LSRT (100 mg/L per day). Renal function, histopathology, TUNEL staining, plasma renin activity (PRA), and the expression of renin and EGF were studied.

Results: Normal rats on the LSD showed significantly increased EGF expression (cortex, 2.6-fold; medulla, 1.7-fold) and significantly decreased EGF expression with the LSRT treatment compared with the rats treated with the NSD (cortex, 74.8 vs. 10%; medulla, 22.5 vs. 5%). In contrast, the CsA-treated rats on the LSD had a significantly lower EGF expression (cortex, 98 vs. 53%; medulla, 94 vs. 14%); however, concomitant administration of LSRT increased the EGF expression (cortex, 91- vs. 3.8-fold; medulla, 19- vs. 2.4-fold) compared with the rats on the NSD. In the normal and CsA-treated LSD rats, EGF expression was well correlated with PRA. In addition, EGF expression was well correlated with the interstitial fibrosis score (r = 0.664, P < 0.01) or number of TUNEL-positive cells (r = 0.822, P < 0.01) in CsA-treated LSD rats.

Conclusions: These results suggest that angiotensin II blockade with LSRT decreases EGF expression in normal rats on the LSD, but it protects EGF expression in CsA-induced nephrotoxicity. This finding provides a new perspective on the renoprotection of angiotensin II blockade in chronic CsA nephrotoxicity.

MeSH terms

  • Angiotensin II / antagonists & inhibitors
  • Animals
  • Apoptosis
  • Blood Pressure / drug effects
  • Cyclosporine / toxicity*
  • Diet, Sodium-Restricted
  • Epidermal Growth Factor / biosynthesis*
  • Epidermal Growth Factor / blood
  • Fibrosis
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Kidney Glomerulus / drug effects*
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Losartan / pharmacology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Renin / blood
  • Renin / metabolism
  • Renin-Angiotensin System / physiology*


  • Angiotensin II
  • Epidermal Growth Factor
  • Cyclosporine
  • Renin
  • Losartan