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AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats

2012; Springer Nature; Volume: 35; Issue: 6 Linguagem: Inglês

10.1038/hr.2012.13

1348-4214

Quaisar Ali, Tahir Hussain,

Sodium Intake and Health

Previously, we demonstrated that angiotensin II type 2 (AT2) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the role of a novel, non-peptide agonist, C21, in natriuresis via AT2 receptor activation in OZR. Infusion of C21 (1 and 5 μg kg−1 min−1) into rats under anesthesia caused a dose-dependent increase in urine flow (UF) and urinary Na volume (UNaV). These effects of C21 were blocked by pre-infusion of the AT2 receptor antagonist, PD123319, (50 μg kg−1 min−1), suggesting involvement of the AT2 receptor. Infusion of C21 (5 μg kg−1 min−1) significantly increased the fractional excretion of sodium without changing the glomerular filtration rate or blood pressure, suggesting a tubular effect. Similarly, C21 infusion increased the fractional excretion of lithium, suggesting a proximal tubular effect. Furthermore, we tested the effect of C21 on natriuresis after blocking two main, distal-nephron Na transporters, the epithelial Na channels (ENaC), with amiloride (AM, 3 mg kg−1 body wt), and the NaCl cotransporters (NCC), with bendroflumethiazide (BFTZ, 7 mg kg−1 body wt). Infusion of AM + BFTZ caused significant increases in both diuresis and natriuresis, which were further increased by infusion of C21 (5 μg kg−1 min−1). Natriuresis in response to C21 was associated with increases in urinary NO and cGMP levels. The data indicate that the AT2 receptor agonist, C21, promotes natriuresis via AT2 receptor activation and that this effect is potentially based in the proximal tubules and linked to the nitric oxide/cyclic guanosine monophosphate pathway. The natriuretic response to C21 may have therapeutic significance by improving kidney function in obesity.