Radicicol, a heat shock protein 90 inhibitor, reduces glomerular filtration rate.
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 HSP90alpha and HSP90beta. More than 100 client proteins have been found to be regulated by HSP90. Several studies have shown that HSP90 regulates nitric oxide 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 (25 microg.ml(-1).min(-1)). Basal levels were taken before experimental measurements. Mean arterial pressure and renal blood flow (RBF) were recorded, as well as GFR, urinary nitrite and nitrate excretion (UNO2/NO3V). Additionally, we evaluated eNOS expression, Ser1177 and Thr495 eNOS phosphorylation levels, the eNOS dimer-to-monomer ratio, as well as oxidative stress by assessing renal lipoperoxidation and urinary isoprostane F(2alpha) 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-to-monomer ratio. Our findings suggest that GFR is in part maintained by HSP90-eNOS interaction.
Ramírez
Victoria
V
Unidad de Fisiología Molecular, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Vasco de Quiroga No. 15, Tlalpan, 14000 Mexico City, Mexico.
Mejía-Vilet
Juan M
JM
Hernández
Damián
D
Gamba
Gerardo
G
Bobadilla
Norma A
NA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects* / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C035359:monorden