Hypercalcemia Reduces Plasma Renin via Parathyroid Hormone, Renal Interstitial Calcium, and the Calcium-Sensing Receptor

Abstract

Acute hypercalcemia inhibits plasma renin activity (PRA). How this occurs is unknown. We hypothesized that acute hypercalcemia inhibits PRA via the calcium-sensing receptor because of parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5. To test our hypothesis, acute in vivo protocols were run in sodium-restricted, anesthetized rats. TRPV5 messenger RNA expression was measured with real-time quantitative RT-PCR. Acute hypercalcemia significantly decreased PRA by 37% from 32.0±3.3 to 20.3±2.6 ng of angiotensin I per milliliter per hour ( P <0.001). Acute hypercalcemia also significantly increased renal cortical interstitial calcium by 38% (1.73±0.06 mmol/L) compared with control values (1.25±0.05 mmol/L; P <0.001). PRA did not decrease in hypercalcemia in the presence of a calcium-sensing receptor antagonist, Ronacaleret (22.8±4.3 versus 21.6±3.6 ng of angiotensin I per milliliter per hour). Increasing plasma calcium did not decrease PRA in parathyroidectomized rats (22.5±2.6 versus 22.0±3.0 ng of angiotensin I per milliliter per hour). Parathyroidectomized rats were unable to increase their renal cortical interstitial calcium in response to hypercalcemia (1.01±0.11 mmol/L). Acutely replacing plasma parathyroid hormone levels did not modify the hypercalcemic inhibition of PRA in parathyroid-intact rats (39.1±10.9 versus 16.3±3.2 ng of angiotensin I per milliliter per hour; P <0.05). Renal cortical TRPV5 messenger RNA expression decreased by 67% in parathyroidectomized ( P <0.001) compared with intact rats. Our data suggest that acute hypercalcemia inhibits PRA via the calcium-sensing receptor because of parathyroid hormone–mediated increases in renal cortical interstitial calcium via TRPV5.