Regulation of glomerulotubular balance. I. Impact of dopamine on flow-dependent transport

Abstract

.-In response to volume expansion, locally generated dopamine decreases proximal tubule reabsorption by reducing both Na/H-exchanger 3 (NHE3) and Na-K-ATPase activity. We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na ϩ and HCO 3 Ϫ reabsorption and have suggested that this observation underlies glomerulotubular balance. In the present work, we investigate the impact of dopamine on the sensitivity of reabsorptive fluxes to changes in luminal flow. Mouse proximal tubules were microperfused in vitro at low and high flow rates, and volume and HCO 3 Ϫ reabsorption (Jv and J HCO3) were measured, while Na ϩ and Cl Ϫ reabsorption (JNa and JCl) were estimated. Raising luminal flow increased J v, JNa, and JHCO3 but did not change J Cl. Luminal dopamine did not change Jv, JNa, and J HCO3 at low flow rates but completely abolished the increments of Na ϩ absorption by flow and partially inhibited the flow-stimulated HCO 3 Ϫ absorption. The remaining flow-stimulated HCO 3 Ϫ absorption was completely abolished by bafilomycin. The DA1 receptor blocker SCH23390 and the PKA inhibitor H89 blocked the effect of exogenous dopamine and produced a two to threefold increase in the sensitivity of proximal Na ϩ reabsorption to luminal flow rate. Under the variety of perfusion conditions, changes in cell volume were small and did not always parallel changes in Na ϩ transport. We conclude that 1) dopamine inhibits flow-stimulated NHE3 activity by activation of the DA1 receptor via a PKA-mediated mechanism; 2) dopamine has no effect on flow-stimulated H-ATPase activity; 3) there is no evidence of flow stimulation of Cl Ϫ reabsorption; and 4) the impact of dopamine is a coordinated modulation of both luminal and peritubular Na ϩ transporters.kidney proximal tubule; sodium chloride and bicarbonate transport; DA1 and DA2 receptor function; torque KIDNEY PROXIMAL TUBULES ARE responsible for reabsorption of ϳ60% of filtered salt and water, and this fractional reabsorption is relatively constant, despite variations in the glomerular filtration rate (GFR). We have sought to understand the mechanism underlying this glomerulotubular balance (GTB) by measuring the impact of tubule perfusion rate on Na ϩ and HCO 3 Ϫ absorption in mouse proximal tubules in vitro. We have previously demonstrated that the afferent signal modulating Na ϩ and HCO 3 Ϫ transport is the flow-dependent torque (bending moment) exerted on brush border microvilli at their base (39) and that this impacts both NHE3-mediated Na ϩ and HCO 3 Ϫ absorption and H-ATPase-mediated H ϩ secretion (17, 19). The mouse proximal tubule cell was also used to examine the cellular mechanism of the flow-induced changes on NHE3 and H-ATPase expression and localization (20). In that system, fluid shear stress induces not only apical NHE3 and H-ATPase but also basolateral side Na-K-ATPase trafficking to the membrane surface. In addition, modulation of NHE3 and Na-KATPase was dependent on an intact actin cytoskeleton, ...

Regulation of glomerulotubular balance: flow-activated proximal tubule function

“…It has been demonstrated that the AT1 receptor is important to maximize the NHE3 activity activated by flow; however, it is not critical for the flow-stimulated HCO 3 − transport, which still exists when the inhibitors are present or when the AT1a receptor is knocked out [15]. Dopamine, which stimulates NHE3 endocytosis via a PKA-dependent mechanism, has no effect on baseline fluxes but abrogates the flow-stimulated Na + and HCO 3 − absorption [18]. A comparison of the changes in torque and changes in transport activity by flow showed that dopamine reduced, and blocking of the dopamine receptor increased the tubule sensitivity to microvillus torque.…”

Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport

“…From these studies we have demonstrated that dopamine completely blocks flowstimulated Na ϩ transport and partially abolishes flow-stimulated HCO 3 Ϫ absorption, and the remaining portion of the increment of HCO 3 Ϫ reabsorption (J HCO3 ) by flow is blocked by the H-ATPase inhibitor bafilomycin. The effects of dopamine were completely abolished by the dopamine DA1 receptor antagonist Sch 23390 (5). We also demonstrated a dopamine-dependent decrease in the sensitivity of the renal brush border to a change in microvillous torque; a DA1 antagonist increased the transport sensitivity to torque.…”

“…Additional studies of mouse tubules in vitro have demonstrated that it is possible for hormonal or autocrine signals to effect either or both baseline transport rates and flow sensitivity. For example, with the application of dopamine, baseline Na ϩ and HCO 3 Ϫ fluxes and the flow sensitivity of each were all reduced by dopamine (5). When the tubules were treated with both dopamine and a DA1 receptor blocker, there were modest increases in baseline flows, but dramatic increases in flow sensitivity for Na ϩ and HCO 3 Ϫ (2.5 and 3.5, respectively).…”

Dopamine D1-like receptors regulate the α1A-adrenergic receptor in human renal proximal tubule cells and D1-like dopamine receptor knockout mice

“…Costimulation of D 1 -and D 2 -like dopamine receptors results in synergism between these receptors to promote diuresis and natriuresis in rats (44). As previously indicated, D 1 -like dopamine receptors and ␣-ARs have opposing effects on Na ϩ transport (4,17,20,73). In the absence of D 1 -like dopamine receptors, the inhibitory effect of D 1 -like receptors on Na ϩ transport is diminished (1), whereas the ␣ 1A -AR predominates (present study).…”