Caveolin-1–eNOS/Hsp70 interactions mediate rosuvastatin antifibrotic effects in neonatal obstructive nephropathy

Abstract

Evidence suggesting that statins may contribute to renoprotection has been provided in experimental 28 and clinical studies. Statins restore endothelial nitric oxide (NO) levels by mechanisms including up-reg- 29 ulation of endothelial NO synthase (eNOS) expression. Caveolin-1/eNOS interaction is essential prevent- 30 ing inadequate NO levels. Here, we evaluated whether caveolin-1 associated with eNOS/Hsp70 31 expression may be involved in the mechanism by which rosuvastatin exerts tubulointerstitial fibrosis 32 protection in neonatal unilateral ureteral obstruction (UUO). Neonatal rats subjected to UUO within 33 2 days of birth and controls were treated daily with vehicle or rosuvastatin (10 mg/kg/day) by oral gavage 34 for 14 days. 35 After UUO, morphometric evaluation of interstitial fibrosis showed increased interstitial volume (Vv) 36 associated with reduced NO availability, increased mRNA and protein caveolin-1 expression as well as 37 downregulation eNOS and heat shock protein 70 (Hsp70) expression. Conversely, rosuvastatin treatment 38 attenuated the fibrotic response linked to high NO availability, decreased mRNA and protein caveolin-1 39 expression, and marked upregulation of eNOS and Hsp70 expression at transcriptional and posttranscrip- 40 tional levels. Moreover, protein?protein interactions determined by immunoprecipitation and by immu- 41 nofluorescence co-localization have shown decreased caveolin-1/eNOS as well as increased Hsp70/eNOS 42 interaction, after rosuvastatin treatment. A dose dependent effect of rosuvastatin on decreased caveolin-1 43 expression was shown in control cortex. 44 In conclusion, our data suggest that statins contribute to the protection against tubulointerstitial fibro- 45 sis injury in neonatal early kidney obstruction by increased NO availability, involving interaction of up- 46 regulated eNOS/Hsp70 and down-regulated caveolin-1.