Caveolin-1-eNOS/Hsp70 interactions mediate rosuvastatin antifibrotic effects in neonatal obstructive nephropathy.
Evidence suggesting that statins may contribute to renoprotection has been provided in experimental and clinical studies. Statins restore endothelial nitric oxide (NO) levels by mechanisms including up-regulation of endothelial NO synthase (eNOS) expression. Caveolin-1/eNOS interaction is essential preventing inadequate NO levels. Here, we evaluated whether caveolin-1 associated with eNOS/Hsp70 expression may be involved in the mechanism by which rosuvastatin exerts tubulointerstitial fibrosis protection in neonatal unilateral ureteral obstruction (UUO). Neonatal rats subjected to UUO within 2 days of birth and controls were treated daily with vehicle or rosuvastatin (10 mg/kg/day) by oral gavage for 14 days. After UUO, morphometric evaluation of interstitial fibrosis showed increased interstitial volume (Vv) associated with reduced NO availability, increased mRNA and protein caveolin-1 expression as well as downregulation eNOS and heat shock protein 70 (Hsp70) expression. Conversely, rosuvastatin treatment attenuated the fibrotic response linked to high NO availability, decreased mRNA and protein caveolin-1 expression, and marked upregulation of eNOS and Hsp70 expression at transcriptional and posttranscriptional levels. Moreover, protein-protein interactions determined by immunoprecipitation and by immunofluorescence co-localization have shown decreased caveolin-1/eNOS as well as increased Hsp70/eNOS interaction, after rosuvastatin treatment. A dose dependent effect of rosuvastatin on decreased caveolin-1 expression was shown in control cortex. In conclusion, our data suggest that statins contribute to the protection against tubulointerstitial fibrosis injury in neonatal early kidney obstruction by increased NO availability, involving interaction of up-regulated eNOS/Hsp70 and down-regulated caveolin-1.
Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
Isabel Mercedes
IM
García
Luciana
L
Mazzei
María Eugenia
ME
Benardón
Liliana
L
Oliveros
Fernando Darío
FD
Cuello-Carrión
Andrea
A
Gil Lorenzo
Walter
W
Manucha
Patricia G
PG
Vallés
D000818:Animals; D000831:Animals, Newborn; D051242:Caveolin 1 / Q000378:metabolism*; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D014517:Ureteral Obstruction
D051242:Caveolin 1; D005464:Fluorobenzenes; D018840:HSP70 Heat-Shock Proteins; D020011:Protective Agents; D011743:Pyrimidines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III