DOPAMINE FAILS TO INHIBIT Na,H-EXCHANGER IN PROXIMAL TUBULES OF OBESE ZUCKER RATS

Abstract

Dopamine via the activation of D1-like receptors inhibits Na,K-ATPase and Na,H-exchanger and subsequently increases sodium excretion. We have previously reported that dopamine failed to inhibit Na,K-ATPase in the proximal tubules (PTs) of obese Zucker rats. The present study was designed to determine the effect of dopamine on Na,H-exchanger in PTs of lean and obese Zucker rats, and examine D1-like receptor-coupled signal transduction pathway mediating the inhibition of Na,H-exchanger. We found that dopamine inhibited Na,H-exchanger in the PTs of lean rats but this response was absent in obese rats. In brush border membranes, [3H]SCH 23390 binding revealed a approximately 45% reduction in D1-like receptor binding sites in obese compared to lean rats. Dopamine stimulated cAMP accumulation in PTs of lean but not in obese rats. Forskolin-mediated stimulation of cAMP was similar in lean and obese rats. Dopamine as well as forskolin and dibutyryl cAMP-mediated stimulation of protein kinase A (PKA) was reduced in PTs of obese compared to lean rats. The data suggest that reduction in D1-like receptor binding sites, defective coupling with signaling pathway and inability of PKA activation may be responsible for the failure of dopamine to inhibit Na,H-exchanger in PTs of obese rats. This phenomenon may contribute to an increase in sodium reabsorption and development of hypertension in obese Zucker rats.

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

“…However, endogenous renal dopamine production is normal or even increased in obese humans (46), monkeys (43), and rats (39). Therefore, the dopaminergic defect in the obese male rat has been suggested to be at the receptor or postreceptor level (4,5,7,23,24,40). Our finding of decreased renal expression of D1R in obese male rats provides a potential explanation for the reduced D1-like dopaminergic signaling previously reported in the proximal tubule of these rats (5,31).…”

“…The impaired natriuretic effect of exogenously administered dopamine in obese Zucker rats has been reported to be caused by impaired ability of D1-like agonists to activate G proteins and inhibit renal sodium/hydrogen exchanger 3 and Na-K-ATPase activities in proximal tubule (8,23,31). On the other hand, increased activity through the D3R, a D2-like receptor, has been reported to be involved in renal injury in obese spontaneously hypertensive NIH corpulent rats (18).…”

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D 1A Receptor in Obese Zucker Rats

“…This may be owing to inability of forskolin to stimulate PKA in proximal tubules of obese rats. 18 Reduced availability of D 1A receptors in the cell could not be a reason because in cytosol D 1A receptor density is not reduced in proximal tubules of obese control rats compared with lean control rats (data not shown). Interestingly, the fact that forskolin recruits D 1A receptors to the plasma membranes in obese rats argues for an alternative PKA-independent pathway for recruiting D 1A receptors to the plasma membrane.…”

Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1receptor dysfunction in obese rats

“…In animal models, dopaminemediated natriuresis is diminished in obese Zucker rats (32,37,39), spontaneously hypertensive rats (16,23), and Dahl saltsensitive rats (27). This phenomenon is associated with decreased ability of dopamine to inhibit both Na ϩ /H ϩ exchanger and Na ϩ -K ϩ -ATPase (31,32,37). …”