Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

Abstract

Olfactory receptors are G protein-coupled receptors that mediate olfactory chemosensation and serve as chemosensors in other tissues. We find that Olfr78, an olfactory receptor expressed in the kidney, responds to short chain fatty acids (SCFAs). Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs. In addition, both Olfr78 and G protein-coupled receptor 41 (Gpr41), another SCFA receptor, are expressed in smooth muscle cells of small resistance vessels. Propionate, a SCFA shown to induce vasodilation ex vivo, produces an acute hypotensive response in wild-type mice. This effect is differentially modulated by disruption of Olfr78 and Gpr41 expression. SCFAs are end products of fermentation by the gut microbiota and are absorbed into the circulation. Antibiotic treatment reduces the biomass of the gut microbiota and elevates blood pressure in Olfr78 knockout mice. We conclude that SCFAs produced by the gut microbiota modulate blood pressure via Olfr78 and Gpr41.

Fig. 1.

Olfr78 is expressed in large renal vessels, renal afferent arterioles, and extrarenal vascular beds. Olfr78 mRNA is detectable in whole kidney by PCR (product was sequenced to confirm identity) (A). Olfr78 expression is localized to large renal vessels by β-galactosidase staining in Olfr78^−/− mice (B and C, 15× magnification). In addition, β-galactosidase signal is found in renal afferent arterioles (D, 100×) and in small resistance vessels in a variety of other tissues, such as the heart (E) and the diaphragm (F). Also see Fig. S1.

Fig. 2.

Olfr78 and its human homolog, OR51E2, traffic to the cell surface when expressed in transfected HEK cells, as shown by surface immunofluorescence (A, 20×; Inset shows higher magnification) and ELISA (B). mOR-EG, which traffics to the surface weakly, is shown for comparison.

Fig. 3.

Screening for ligands showed that Olfr78 responded only to mix OxlK (A), and that the component of OxlK eliciting a response was acetic acid (B). A screen using chemically similar compounds showed that Olfr78 responded to acetate and propionate, but not to other related compounds (C). Dose–response curves for Olfr78 and OR51E2 are shown in D and E, respectively.

Fig. 4.

Olfr78 expression is detectable by PCR (A) in a preparation of microdissected glomeruli/JGAs (expected size: 614 nt; product was sequenced to confirm identity). Propionate (P) induces quinacrine release (which is a surrogate for renin release) in wild-type but not Olfr78^−/− animals (B). PRA levels (plasma renin activity, normalized ex vivo to wild-type and determined as the slope of the time course of fluorescent product production in a kinetic assay) (27, 28) are significantly reduced in Olfr78^−/− mice (C). * indicates statistical significance.

Fig. 5.

Propionate causes a drop in BP in wild-type animals that is both reproducible (A) and dose dependent (B). In Olfr78^−/− mice, this response is accentuated at low propionate doses (C). In addition to Olfr78, SCFA receptors Gpr41 and Gpr43 are also expressed in the vasculature, as revealed by RT-PCR analysis of mRNA prepared from iliac arteries, renal arteries, and aortas of wild-type and Olfr78^−/− mice (D). In Gpr41^−/− mice, the response to propionate is blunted. Whereas 10 mM propionate produces a hypotensive effect in Gpr41^+/− mice, no such hypotensive effect is detected in the Gpr41^−/− mice (E). Treatment with orally administered antibiotics produced a marked reduction in microbial biomass in the gut (Figs. S4 and S5). This reduction was associated with significantly increased systolic (sys), diastolic (dias), and mean arterial blood pressure (MAP) in Olfr78^−/− animals, but not in wild-type animals (F) (P < 0.04 vs. wild type). * indicates statistical significance.