Published Online
on April 21, 2003

A more recent version of this article appeared on June 1, 2003

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Submitted on January 17, 2003
Revised on February 14, 2003

Dopamine-Mediated Inhibition of Renal Na,K-ATPase Is Reduced by Insulin

Anees Ahmad Banday; Mohammad Asghar; Tahir Hussain; and Mustafa F. Lokhandwala^*

From the Heart and Kidney Institute, University of Houston, Houston, Tex.

^* To whom correspondence should be addressed. E-mail: mlokandwala{at}uh.edu.

Abstract--Recently we have reported that rosiglitazone treatment of obese Zucker rats reduced plasma insulin and restored the ability of dopamine to inhibit Na,K-ATPase (NKA) in renal proximal tubules. The present study was performed to test the hypothesis that a chronic increase in levels of insulin causes a decrease in expression of the D1 receptor and its uncoupling from G proteins, which may account for the diminished inhibitory effect of dopamine on NKA in obese Zucker rats. We conducted experiments in primary proximal tubule epithelial cells obtained from Sprague-Dawley rat kidneys. These cells at 80% to 90% confluence were pretreated with insulin (100 nmol/L for 24 hours) in growth factor-/serum-free medium. SKF-38393, a D1 receptor agonist, inhibited NKA activity in untreated cells, but the agonist failed to inhibit enzyme activity in insulin-pretreated cells. Basal NKA activity was similar in untreated and insulin-pretreated cells. Measurement of D1 receptors in the plasma membranes revealed that [³H]SCH-23390 binding, a D1 receptor ligand, as well as D1 receptor protein abundance, was significantly reduced in insulin-pretreated cells compared with untreated cells. SKF-38393 (10 µmol/L) elicited significant stimulation of [³⁵S]GTPS binding in the membranes from control cells, suggesting that the D1 receptor-G protein coupling was intact. However, the stimulatory effect of SKF-38393 was absent in membranes from insulin-pretreated cells. We suggest that chronic exposure of cells to insulin causes both the reduction in D1 receptor abundance and its uncoupling from G proteins. These phenomena might account for the diminished inhibitory effect of dopamine on NKA activity in hyperinsulinemic rats.

Key words: dopamine • insulin • Na⁺-K⁺-transporting ATPase • receptors, dopamine • G proteins

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