Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension

Jan 25, 2021Hypertension (Dallas, Tex. : 1979)

Lack of a Kidney Receptor Reduces Salt Transporter Activity in High Blood Pressure Caused by Angiotensin II

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Abstract

Global NPR-C deficiency attenuated Ang II-induced increased blood pressure in both male and female mice.

NPR-C variants may be linked to elevated blood pressure as identified in genome-wide association studies.
Continuous Ang II infusion led to increased renal NPR-C expression in wild-type mice.
Diuretic and natriuretic responses to saline were enhanced in NPR-C deficient mice.
Ang II stimulation increased abundance and phosphorylation of the NaCl cotransporter (NCC), which was reduced by NPR-C deletion.
Hydrochlorothiazide did not induce natriuresis in NPR-C knockout mice.
The signaling pathways involving WNK4/SPAK/NCC and NPR-C/Gi/PLC/PKC may mediate NCC activation in response to Ang II.

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Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II-induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets-induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II-induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension.

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Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension

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