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Am J Physiol Renal Physiol (November 2, 2004). doi:10.1152/ajprenal.00227.2004
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Submitted on June 21, 2004
Accepted on October 25, 2004

Abnormal EGF-dependent regulation of sodium absorption in ARPKD collecting duct cells

I. Elias Veizis1* and Calvin U. Cotton1

1 Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA

* To whom correspondence should be addressed. E-mail: ev{at}po.cwru.edu.

Amiloride-sensitive sodium entry, via the epithelial sodium channel (ENaC), is the rate limiting step for Na+ absorption in kidney collecting ducts and epidermal growth factor (EGF)inhibits Na+ transport and ENaC expression. A pathognomonic feature of polycystic kidney disease (PKD) is EGF receptor mislocalization to the apical plasma membrane and EGF/EGF receptor axis overactivity. Immunohistochemical and biochemical analysis revealed mislocalization of EGF receptor and excessive activation of the p42/44 extracellular signal-regulated protein kinase pathway (ERK1/2) in kidneys from cystic mice compared to non-cystic littermates. Primary monolayer cultures of non-cystic and cystic murine collecting duct principal cells were used to identify aberrant EGF-dependent ERK1/2 activation and regulation of Na+ transport associated with autosomal recessive PKD. Addition of EGF to the basolateral bathing solution of non-cystic or cystic monolayers lead to p42/44 phosphorylation and inhibition of Na+ transport (30-35%); whereas apical EGF was effective only in monolayers derived from cystic mice. p42/44 phosphorylation and inhibition of Na+ transport were prevented by prior treatment of the cells with an ERK kinase inhibitor. Chronic treatment (24hrs) of non-cystic and cystic monolayers with basolateral EGF elicited sustained inhibition of Na+ absorption (50-55%) and a reduction in steady-state ENaC mRNA levels (50-75%). In contrast, addition of EGF to the apical bathing solution (24hrs) had no effect in non-cystic monolayers but lead to inhibition of Na+ transport (50-60%) and decreased ENaC expression (45-60%) in cystic cells. Pretreatment of the monolayers with an ERK kinase inhibitor abolished the chronic effects of EGF on Na+ transport. The results of these studies reveal that the mislocalized apical EGF receptors are functionally coupled to the ERK pathway and that abnormal EGF-dependent regulation of ENaC function and expression may contribute to PKD pathophysiology.




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