Faculty Opinions recommendation of Improvement of renal hemodynamics during hypertension-induced chronic renal disease: role of EGF receptor antagonism.

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 NG-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.

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Evolving role of growth factors in the renal response to acute and chronic disease.

Journal of the American Society of Nephrology ◽

10.1681/asn.v271163 ◽

1992 ◽

Vol 2 (7) ◽

pp. 1163-1170

Author(s):

L G Fine ◽

M R Hammerman ◽

H E Abboud

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Renal Disease ◽

Egf Receptor ◽

Chronic Renal Disease ◽

Collecting Duct ◽

Platelet Derived Growth Factor ◽

Glomerular Mesangial Cells ◽

Hypertrophic Growth

The roles of growth factors in the pathogenesis of various forms of acute and chronic renal disease are largely putative. Nevertheless, there is a growing body of information that links specific growth factors to particular forms of renal injury. In all instances, it is supposed that such associations are not necessarily unique and that multiple cytokines probably interact to determine the pattern of injury or the regenerative response to such injury. Regeneration of tubular epithelium after acute tubular necrosis involves upregulation of the epidermal growth factor (EGF) receptor. Early studies of exogenously administered EGF indicate that the severity and duration of renal failure may be attenuated by this growth factor. Thus far, the observed responses have been limited and the role of EGF as a therapeutic agent requires more study. The mechanism of generation of tubulointerstitial injury in most forms of renal disease is difficult to understand. Early in vitro studies of growth factor production by tubular cells (in the absence of any infiltrating cells) indicate that platelet-derived growth factor produced by the medullary collecting duct is mitogenic for renal medullary fibroblasts, suggesting a paracrine growth system in this region of the kidney. Insulin-like growth factor I has also been shown to be produced by collecting duct cells. Its production is increased by EGF, and its association with certain forms of renal hypertrophy, i.e., diabetes and hypersomatotrophic states, implies its participation in the hypertrophic growth response. Platelet-derived growth factor is a potent mitogen for glomerular mesangial cells, and its production is regulated by a variety of cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)

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