Submitted on April 29, 2008
Revised on July 23, 2008
Accepted on July 24, 2008
Radicicol, a Heat Shock Protein 90 (Hsp90) Inhibitor, Reduces Glomerular Filtration Rate
Victoria Ramirez, Juan M Mejia-Vilet, Damian Hernandez, Gerardo Gamba1, and Norma A. Bobadilla2*
1 Inst Nacional de la Nutrition Salvador Zubiran
2 Universidad Nacional Autonoma de Mexico
* To whom correspondence should be addressed. E-mail: nab{at}biomedicas.unam.mx.
The heat shock protein subfamily of 90 kDa (Hsp90) is composed of five isoforms. The more abundant proteins of this subfamily are cytosolic isoforms known as Hsp90
and Hsp90
. More than 100 client proteins have been found to be regulated by Hsp90. Several studies have shown that Hsp90 regulates NO synthesis that is dependent on endothelial nitric oxide synthase (eNOS). Because eNOS regulates renal vascular tone and glomerular filtration rate (GFR), the present study was designed to evaluate the effect of acute Hsp90 inhibition with radicicol on GFR and the eNOS pathway. Twenty male Wistar rats were divided into two groups: control vehicle animals and radicicol-infused animals at 25µg/ml/min. Basal levels were taken before experimental measurements. Mean arterial pressure (MAP) and renal blood flow (RBF) were recorded, as well as GFR, urinary nitrites and nitrate excretion (UNO2/N03V). Additionally, we evaluated eNOS expression, Ser1177, and Thr495 eNOS phosphorylation levels, the eNOS dimer/monomer ratio as well as oxidative stress by assessing renal lipoperoxidation and urinary isoprostanes F2 and hydrogen peroxide. Hsp90 inhibition with radicicol produced a fall in RBF and GFR that was associated with a significant reduction of UNO2/NO3V. The effects of radicicol were in part mediated by a significant decrease in eNOS phosphorylation and in the eNOS dimer/monomer ratio. Our findings suggest that GFR is in part maintained by Hsp90-eNOS interaction.
