Abstract 1101: Acetyl-Seryl-Aspartyl-Lysyl-Proline Mediates Part of the Renal Antifibrotic Effect of Angiotensin-Converting Enzyme Inhibitor in Aldosterone-Salt-Induced Hypertension
We reported that acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) reduced renal fibrosis and cell proliferation in rats with aldosterone (ALDO)-salt-induced hypertension. Others reported that an angiotensin-converting enzyme inhibitor (ACEi) prevented renal fibrosis in this model. Recently we found that the antifibrotic effect of ACEi in the heart was partly mediated by Ac-SDKP in rats with angiotensin-induced hypertension. Thus we tested whether the antifibrotic effect of ACEi in the kidney is mediated by Ac-SDKP in ALDO-salt hypertension. An anti-Ac-SDKP monoclonal antibody (mAb) was used to block the effect of Ac-SDKP. SD rats (BW: 310 g) were divided into:
ALDO-salt + vehicle,
ALDO-salt + captopril (100 mg/kg/d in drinking water),
ALDO-salt + captopril + mAb (400 μg/kg, i.p. every other day),
ALDO-salt + Ac-SDKP (800 μg/kg/d), and
ALDO-salt + Ac-SDKP + mAb.
ALDO (0.75 μg/hr) or Ac-SDKP was given s.c. via osmotic minipump and salt (1% NaCl/0.2% KCl) in drinking water. Treatment lasted for 6 weeks. As expected, ALDO-salt induced renal fibrosis (hydroxyproline assay), glomerular matrix expansion (periodic acid-Schiff (PAS) staining) and increased phosphorylated p42/44 mitogen-activated protein kinase (MAPK) (P-p42/44) (Western blot). ACEi and Ac-SDKP significantly reduced renal fibrosis and glomerular expansion (p < 0.05) but not hypertension or renal hypertrophy; while mAb reduced the antifibrotic effects of ACEi or Ac-SDKP on the kidney. ACEi and Ac-SDKP also significantly reduced renal P-p42/44, and mAb blunted this decrease. Phosphorylated p38 or JNK MAPK was not detectable. We concluded that the antifibrotic effect of ACEi in the kidney is at least partly mediated by Ac-SDKP in ALDO-salt hypertension via inhibition of the p42/44 MAPK pathway.