The olfactory isoform of adenylyl cyclase (AC3) in the renal macula densa serves as a key regulator of glomerular filtration rate

Abstract

Recent work shows that olfactory receptors (ORs) are functionally expressed in non‐olfactory tissues. We find that key components of the OR signaling pathway, olfactory G protein (Golf) and the olfactory adenylyl cyclase (AC3), are detectable in the kidney by RT‐PCR and western blot. AC3 and Golf colocalize with one another and with markers of the distal convoluted tubule. Most notably, AC3 is expressed in the macula densa (MD). The MD regulates glomerular filtration rate (GFR) through both the tubuloglomerular feedback (TGF) and renin secretion pathways. Renal function studies using AC3−/− mice and wild‐type littermates demonstrated that GFR in AC3−/− mice is significantly decreased (AC3−/−:0.42 ± 0.08 ml/min/100g BW, n=8; AC3+/+: 0.87 ± 0.06, n=6, p<0.01). This is not due to alterations in TGF, as TGF assayed by micropuncture is normal in AC3−/−; however, AC3−/− have a ~50% reduction in plasma renin concentration (p<0.001). By RT‐PCR, we have identified six ORs in mouse kidney, suggesting that the chemosensors that participate in this pathway are also present in renal epithelia. These studies indicate that the olfaction machinery present in the kidney is necessary for proper control of GFR, presumably through modulation of renin secretion to regulate efferent arteriolar diameter. This OR machinery is found in the MD, an ideal localization for ORs to sense the chemical composition of the forming urine.