Submitted on January 12, 2009
Revised on April 3, 2009
Accepted on May 4, 2009
IMPROVEMENT OF RENAL HEMODYNAMICS DURING HYPERTENSION-INDUCED CHRONIC RENAL DISEASE: ROLE OF EGF RECEPTOR ANTAGONISM
Frank Helle, Charlotte Jouzel, Christos Chadjichristos, Sandrine Placier, Martin Flamant, Dominique Guerrot, Helene Francois, Jean-Claude Dussaule, and Christos Chatziantoniou1*
1 Hopital Tenon
* To whom correspondence should be addressed. E-mail: christos.chatziantoniou{at}chusa.jussieu.fr.
The present study investigated mechanisms of regression of renal disease after severe proteinuria by focusing on the interaction between Epidermal Growth Factor Receptor (EGFR), 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/mmolCreat, animals were divided in three groups for an experimental period of therapy of 2 weeks; 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 EGFR 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 EGFR antagonist did not have an additional effect on lowering blood pressure, neither on renal inflammation, but normalized 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 re-appeared 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. EGFR is an important mediator of endothelial dysfunction and contributes to the decline of RBF in the chronic kidney disease induced by NO deficiency. The EGFR 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 is necessary to apply AT1 receptor antagonism.
