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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/F191    most recent 00015.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Helle, F. Articles by Chatziantoniou, C. PubMed PubMed Citation Articles by Helle, F. Articles by Chatziantoniou, C.

Improvement of renal hemodynamics during hypertension-induced chronic renal disease: role of EGF receptor antagonism

¹INSERM U702, Hôpital Tenon, ²Pierre et Marie Curie University, and ³Assistance Publique-Hôpitaux de Paris, Laboratoire de Physiologie, Hôpital St.-Antoine, Paris, France

Submitted 12 January 2009 ; accepted in final form 4 May 2009

The present study investigated mechanisms of regression of renal disease after severe proteinuria by focusing on the interaction among EGF receptors, renal hemodynamics, and structural lesions. The nitric oxide (NO) inhibitor N^G-nitro-L-arginine-methyl ester (L-NAME) was administered chronically in Sprague-Dawley rats. When proteinuria exceeded 2 g/mmol creatinine, animals were divided into three groups for an experimental period of therapy of 2 wk; in one group, L-NAME was removed to allow reactivation of endogenous NO synthesis; in the two other groups, L-NAME removal was combined with EGF or angiotensin receptor type 1 (AT₁) antagonism. L-NAME removal partially reduced mean arterial pressure and proteinuria and increased renal blood flow (RBF), but not microvascular hypertrophy. Progression of structural damage was stopped, but not reversed. The administration of an EGF receptor antagonist did not have an additional effect on lowering blood pressure or on renal inflammation but did normalize RBF and afferent arteriole hypertrophy; the administration of an AT₁ antagonist normalized all measured functional and structural parameters. Staining with a specific marker of endothelial integrity indicated loss of functional endothelial cells in the L-NAME removal group; in contrast, in the animals treated with an EGF or AT₁ receptor antagonist, functional endothelial cells reappeared at levels equal to control animals. In addition, afferent arterioles freshly isolated from the L-NAME removal group showed an exaggerated constrictor response to endothelin; this response was blunted in the vessels isolated from the EGF or AT₁ receptor antagonist groups. The EGF receptor is an important mediator of endothelial dysfunction and contributes to the decline of RBF in the chronic kidney disease induced by NO deficiency. The EGF receptor antagonist-induced improvement of RBF is important but not sufficient for a complete reversal of renal disease, because it has little effect on renal inflammation. To achieve full recovery, it is necessary to apply AT₁ receptor antagonism.

angiotensin; fibrosis; proteinuria; regression