title: Small-Molecule Inhibitors of Pendrin Potentiate the Diuretic Action of Furosemide.
abstract: Pendrin is a Cl-/HCO3-exchanger expressed in type B and non-A, non-B intercalated cells in the distal nephron, where it facilitates Cl-absorption and is involved in Na+absorption and acid-base balance. Pendrin-knockout mice show no fluid-electrolyte abnormalities under baseline conditions, although mice with double knockout of pendrin and the Na+/Cl-cotransporter (NCC) manifest profound salt wasting. Thus, pendrin may attenuate diuretic-induced salt loss, but this function remains unconfirmed. To clarify the physiologic role of pendrin under conditions not confounded by gene knockout, and to test the potential utility of pendrin inhibitors for diuretic therapy, we tested in mice a small-molecule pendrin inhibitor identified from a high-throughput screen. In vitro, a pyrazole-thiophenesulfonamide, PDSinh-C01, inhibited Cl-/anion exchange mediated by mouse pendrin with a 50% inhibitory concentration of 1-3 µM, without affecting other major kidney tubule transporters. Administration of PDSinh-C01 to mice at predicted therapeutic doses, determined from serum and urine pharmacokinetics, did not affect urine output, osmolality, salt excretion, or acid-base balance. However, in mice treated acutely with furosemide, administration of PDSinh-C01 produced a 30% increase in urine output, with increased Na+and Cl-excretion. In mice treated long term with furosemide, in which renal pendrin is upregulated, PDSinh-C01 produced a 60% increase in urine output. Our findings clarify the role of pendrin in kidney function and suggest pendrin inhibition as a novel approach to potentiate the action of loop diuretics. Such combination therapy might enhance diuresis and salt excretion for treatment of hypertension and edema, perhaps including diuretic-resistant edema.
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California.
authors.forename: Onur
authors.initials: O
authors.lastname: Cil
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haggie
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California.
authors.forename: Joseph-Anthony
authors.initials: JA
authors.lastname: Tan
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California Alan.Verkman@ucsf.edu.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000037:antagonists & inhibitors*; D004232:Diuretics / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005665:Furosemide / Q000494:pharmacology*; D051379:Mice; D000076988:Sulfate Transporters; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D027321:Anion Transport Proteins; D004232:Diuretics; C000619500:PDS(inh)-C01; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D013449:Sulfonamides; D013876:Thiophenes; D005665:Furosemide
keywords: cell & transport physiology; collecting ducts; diuretics; water-electrolyte balance