Defective D1-like receptor-mediated inhibition of the Cl−/HCO3−exchanger in immortalized SHR proximal tubular epithelial cells

Abstract

The sensitivity of the Cl−/HCO3−exchanger to dopamine D1- and D2-like receptor stimulation in immortalized renal proximal tubular epithelial cells from the spontaneous hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) was examined. The activity of the Cl−/HCO3−exchanger (in pH U/s) in SHR cells (0.00191) was greater than in WKY cells (0.00126). The activity of Cl−/HCO3−exchanger was exclusively observed at the apical cell side and probably occurs through the SLC26A6 anion transporter that is expressed in both WKY and SHR cells. Stimulation of D1-like receptors with SKF-38393 markedly attenuated the HCO3−-dependent intracellular pH recovery in WKY cells but not in SHR cells. Stimulation of D2-like receptors with quinerolane did not alter Cl−/HCO3−exchanger activity in both WKY and SHR cells. The selective D1-like receptor antagonist SKF-83566 prevented the effect of SKF-38393. Both WKY and SHR cells responded to dibutyryl-cAMP (DBcAMP) with inhibition of the Cl−/HCO3−exchanger, and downregulation of PKA (overnight exposure to DBcAMP) abolished the inhibitory effect of both DBcAMP and SKF-38393 in WKY cells. Both SHR and WKY cells responded to forskolin with increases in the formation of cAMP. However, only WKY responded to SKF-38393 with increases in the formation of cAMP that was prevented by SKF-83566. It is concluded that WKY cells respond to D1-like dopamine receptor stimulation with inhibition of the apical Cl−/HCO3−(SLC26A6) exchanger and SHR cells have a defective D1-like dopamine response.