Renal Olfactory Receptor 90 (Olfr90) Responds to Fungal Metabolites
Halperin Kuhns RL, Pluznick JL
Receptors that help detect smells often have no known ligand, the molecule that turns them on, so to speak. That makes them orphan receptors. As these receptors are found well outside of the nose, we have to figure out what they react with to try and understand their function.
First we need a bit of vocabulary to study the family tree. Olfactory receptors have families, even though they may not have parents. Structurally similar receptors often have overlap in their ligands, as may less similar receptors found in the same tissues. When ligands for an orphan receptor are identified, the receptor is “de-orphanized” (why don’t we say adopted and complete the damn metaphor, please?).
Olfr90 is an orphan olfactory receptor, found in the macula densa of the kidney. After expressing this molecule in a cell line with a reporter so cells would glow when the receptor got turned on, these investigators exposed these cells to a number of potential ligands. These included mixtures of odorant chemicals (after all, these are olfactory receptors), common ligands for “siblings” of the receptor, physiologically relevant ligands of “sibling” receptors, and physiologically relevant odorants. This strategy produced 9 ligands with little in common structurally; however, 4 of the 9 represented fungal metabolic products. When tested against other fungal-derived metabolites as well as conditioned media from various fungi, an additional 7 ligands occurred. Thus, 11 of 16 ligands for Olfr90 are of fungal origin.
So why does the kidney need to react to fungus? After all, this is an internal organ that should not regularly be exposed to yeasty-beasties, even though those wily single-cells run all over out skin and guts. Kidney and urinary tract infections with fungus do occur, but generally in immunosuppressed patients or those with instrumented urinary tracts. Making receptors has metabolic costs for cells, so should have a benefit beyond a relatively rare infection risk.
As noted last at the Cannon Lecture, microbes do not always have to enter the body to wreck havoc. Under certain circumstances the gut and other mucosa can become “leaky” and allow microbial metabolites into the circulation. These sensors may be waiting for the metabolites as a signal of these processes.
So what response does the kidney make to these ligands? Experiments are still in progress, but given the Olfr90 localization to the macula densa, changes in glomerular filtration rate could occur.
Study of olfactory receptors opens a world well beyond the nose. They do not mean the kidney smells, in any sense of the word!