Abstract
Blood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. Renin secretion stimulated by renal sympathetic neurons is considered essential to this process; however, its regulatory mechanism remains largely unknown. Here, we show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg2+-permeable cation channel, in augmenting renin secretion in the active period. TRPM6 expression is significantly reduced in the distal convoluted tubule of hypotensive Cnnm2-deficient mice. We generate kidney-specific Trpm6-deficient mice and observe a decrease in blood pressure and a disappearance of its circadian variation. Consistently, renin secretion is not augmented in the active period. Furthermore, renin secretion after pharmacological activation of β-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells. These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure.
Highlights
Blood pressure has a daily pattern, with higher values in the active period
Immunoblotting analyses of kidney lysates confirmed a significant decrease of transient receptor potential melastatin-related 6 (TRPM6) at the protein level by Cnnm2deficiency, while the levels of Na-Cl co-transporter (NCC) and phosphorylated NCC were not markedly affected (Supplementary Fig. 1b, CNNM2 expression was confirmed by successive immunoprecipitation and immunoblotting analyses)
The decrease of TRPM6 in the kidneys of Cnnm2fl/fl;Six2-Cre mice was confirmed by immunofluorescence analyses (Supplementary Fig. 1c)
Summary
Blood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. We show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg2+-permeable cation channel, in augmenting renin secretion in the active period. Renin secretion after pharmacological activation of β-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure. 1234567890():,; Approximately one billion people worldwide are estimated to have hypertension, which significantly increases the risk of various diseases, including potentially fatal diseases, such as ischemic heart disease and stroke These hypertension-related fatal incidents are known to occur frequently in the early morning, the beginning of the active period when blood pressure rises sharply[1].
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