Functional role of histamine receptors in the renal cortical collecting duct cells

• Published in: American Journal of Physiology: Cell Physiology Vol. 322; no. 4; pp. C775 - C786
• Main Authors: Sudarikova, Anastasia V, Fomin, Mikhail V, Sultanova, Regina F, Zhao, Ying, Perez, Samantha, Domondon, Mark, Shamatova, Margarita, Lysikova, Daria V, Spires, Denisha R, Ilatovskaya, Daria V
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2022
• Series: Advances in GPCRs: Structure, Mechanisms, Disease, and Pharmacology
• Subjects: Animals; Blood pressure; Calcium (intracellular); Collecting duct; Epithelial Sodium Channels - metabolism; Gastric juice; Gene expression; Histamine; Histamine receptors; Hypersensitivity; Immunocytochemistry; Immunomodulation; Inflammation; Kidney Tubules, Collecting - metabolism; Kidneys; Mice; Nephrons - metabolism; Neurotransmission; Reabsorption; Receptors, Histamine - genetics; Receptors, Histamine - metabolism; Short-circuit current; Sodium - metabolism; epithelial Na+ channels; kidney; histamine; collecting duct; histamine receptors
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00420.2021

Histamine is an important immunomodulator, as well as a regulator of allergic inflammation, gastric acid secretion, and neurotransmission. Although substantial histamine level has been reported in the kidney, renal pathological and physiological effects of this compound have not been clearly defined. The goal of this study was to provide insight into the role of histamine-related pathways in the kidney, with emphasis on the collecting duct (CD), a distal part of the nephron important for the regulation of blood pressure. We report that all four histamine receptors (HRs) as well as enzymes responsible for histamine metabolism and synthesis are expressed in cultured mouse mpkCCD cells, and histamine evokes a dose-dependent transient increase in intracellular Ca in these cells. Furthermore, we observed a dose-dependent increase in cAMP in the CD cells in response to histamine. Short-circuit current studies aimed at measuring Na reabsorption via ENaC (epithelial Na channel) demonstrated inhibition of ENaC-mediated currents by histamine after a 4-h incubation, and single-channel patch-clamp analysis revealed similar ENaC open probability before and after acute histamine application. The long-term (4 h) effect on ENaC was corroborated in immunocytochemistry and qPCR, which showed a decrease in protein and gene expression for αENaC upon histamine treatment. In summary, our data highlight the functional importance of HRs in the CD cells and suggest potential implications of histamine in inflammation-related renal conditions. Further research is required to discern the molecular pathways downstream of HRs and assess the role of specific receptors in renal pathophysiology.