Fig. 3.

Integrated renal and blood pressure phenotype of P2Y₂ receptor knockout mice. The renal expression and activity of Na-K-2Cl cotransporter (NKCC2) and aquaporin-2 (AQP2) are enhanced in P2Y₂−/− mice, which increases NaCl and fluid reabsorption via these pathways. The increased ENaC P_o also facilitates Na⁺ reabsorption. Impaired renal NaCl and fluid excretion increases the effective circulating volume (ECV), which enhances blood pressure (BP) and suppresses renal sympathetic nerve activity (RSNA) and the renin-angiotensin-aldosterone-system (RAS). Activation of baroreceptors (BR) reduces heart rate (HR) to lower BP. Suppression of aldosterone downregulates ENaC expression, which compensates for a greater P_o and normalizes net Na⁺ reabsorption via ENaC. We speculate that lower RSNA and the greater BP via pressure natriuresis (54) inhibit proximal tubular reabsorption of NaCl and fluid. Since the glomerular filtration rate and thus the filtration of NaCl and fluid are normal in P2Y₂−/− mice, this induces greater deliveries of NaCl and fluid out of the proximal tubule. Greater NaCl reabsorption via NKCC2 in water-impermeable TAL normalizes net NaCl delivery but causes the delivery of greater amounts of more hypotonic fluid to the early distal convoluted tubule. When the vasopressin system and thus the distal water permeability are suppressed, the latter facilitates free water clearance. Under basal conditions, however, the excess water is reabsorbed via increased AQP2 activity, such that net urinary NaCl and fluid excretion is normal in P2Y₂−/− mice. The inhibitory influence of P2Y₂ receptors on vascular tone is not illustrated. Modified from Ref. 69.