Abstract
Arterial hypertension, is a common disorder with multiple and variable etiologies. Single nucleotide polymorphism analyses have detected an association between variants in the gene encoding the electrogenic Na+:HCO3– cotransporter NBCe2 (Slc4a5), and salt-sensitive hypertension. Mice with genetic deletion of NBCe2 are hypertensive, and the cause of the blood pressure (BP) increase is believed to arise from a lack of renal NBCe2 function. The exact cellular expression of NBCe2 in the kidney tubular system is, however, not determined. Here, we find NBCe2 to be expressed predominantly in isolated connecting tubules (CNT) and cortical collecting ducts (CD) by RT-PCR. In isolated renal CNT and CCD, genetic deletion of NBCe2 leads to decreased net base extrusion. To determine the role of renal NBCe2 in the development of hypertension, we generated CNT and intercalated cell NBCe2 knockout mice by crossing an Slc4a5 lox mouse with mice expressing cre recombinase under the V-ATPase B1 subunit promotor. Although the mice displayed changes in the expression of renal membrane transporters, we did not detect hypertension in these mice by tail cuff recordings. In conclusion, while global NBCe2 deletion certainly causes hypertension this study cannot confirm the role of renal NBCe2 expression in blood pressure regulation.
Highlights
Hypertension, defined as a chronically elevated blood pressure (BP), is one of the most common chronic disorders in the developed world, affecting nearly one billion people worldwide (Writing Group Members et al, 2016)
Our study suggests that a lack of NBCe2 expression in the connecting tubules (CNT) and collecting ducts (CD) does not seem to be associated with the hypertension observed in global NBCe2 knockouts
Most fractions showed contamination from other tubular segments, NBCe2 expression only coincided with distal convoluted tubules (DCT), or CNT/CCD markers
Summary
Hypertension, defined as a chronically elevated blood pressure (BP), is one of the most common chronic disorders in the developed world, affecting nearly one billion people worldwide (Writing Group Members et al, 2016). Slc4a5, encoding the sodium bicarbonate cotransporter NBCe2, was shown to be significantly associated with BP increases (Barkley et al, 2004; Hunt et al, 2006), and a salt-sensitivity trait (Carey et al, 2012; Taylor et al, 2012) by several genome wide association studies. Studies of NBCe2 knockout (NBCe2 ko) mice confirmed this observation. In the pioneering study by Groger et al (2012) an NBCe2 ko was generated by excising the 7th coding exon, which resulted in increased BP at day and night time, metabolic acidosis, increased arterial natriuretic peptide, hyporeninemia, hypoaldosteronism, and increased glomerular filtration rate. A quite different phenotype was observed in the studies by Wen et al (2015b) in the same ko model, but backcrossed to a C57Bl/6 background for at least 6
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