Cell Biology – Immunology – Pathology

Kidney International (2005) 68, 2131–2142; doi:10.1111/j.1523-1755.2005.00669.x

Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage

BERNARDO RODRÍGUEZ-ITURBE, ATILIO FERREBUZ, VALENTINA VANEGAS, YASMIR QUIROZ, FABIANA ESPINOZA, HECTOR PONS and NOSRATOLA D VAZIRI

Renal Service, Hospital Universitario, Universidad del Zulia, Instituto de Investigaciones Biomédicas (INBIOMED) Maracaibo, Venezuela; and Division of Nephrology and Hypertension, University of California Irvine, Irvine, California

Correspondence: Bernardo Rodriguez-Iturbe, Servicio de Nefrología, 9° Piso, Hospital Universitario, Avenida Guajira s/n, Maracaibo 4001-A, Venezuela. E-mail: bernardori@telcel.net.ve

Received 24 April 2005; Revised 8 June 2005; Accepted 28 June 2005.

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Abstract

Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage.

Background

 

Chronic renal disease is associated with oxidative stress and reduced nitric oxide availability which, in turn, promotes hypertension and further progression of renal damage. Most actions of nitric oxide are mediated by cyclic 3',5' guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases (PDE). Therefore, we investigated if inhibition of PDE-5 would retard the progression of chronic renal failure.

Methods

 

We studied rats with 5/6 nephrectomy treated with sildenafil (2.5 mg/kg-1/day-1) in two experimental protocols. In the first protocol, we started sildenafil therapy immediately after renal ablation and continued treatment for 8 weeks. Control groups consisted of rats with renal ablation treated with drug-free vehicle and sham-operated rats with and without sildenafil treatment.

Results

 

In these studies, sildenafil treatment prevented hypertension and deterioration of renal function, reduced histologic damage, inflammation and apoptosis, delayed the onset of proteinuria, and preserved renal capillary integrity. In the second protocol we compared sildenafil with losartan (7.5 mg/kg-1/day-1) and the combination of both drugs in established renal disease, starting these drugs 4 weeks after 5/6 nephrectomy. Delayed sildenafil treatment failed to improve proteinuria and glomerulosclerosis but ameliorated hypertension and azotemia.

Conclusion

 

These observations suggest that currently available PDE-5 inhibitors have potential clinical value in the treatment of chronic renal disease.

Keywords:

phosphodiesterase-5 inhibition, chronic renal disease, inflammation, hypertension, lymphocytes, macrophages, sildenafil

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