Functional Relevance of Renal Histamine Receptors in the Kidney

The immunology of kidney disease is complex and involves factors from both the innate and the adaptive immune systems. Histamine is an important immunomodulator, as well as a regulator of allergic inflammation, gastric acid secretion, and neurotransmission. Although an increase in histamine level and expression of histamine-metabolizing enzymes have been shown in the kidney, renal pathological and physiological effects of histamine have not been clearly defined. The goal of this study was to provide insight into the physiological importance of the 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. To address the goal of the project, we first tested histamine receptors’ (HRs) expression in the CD cells; all 4 receptors were found to be expressed in the cultured CD cells, as well as in the rat kidney. Next, we showed that histamine evokes a dose-dependent transient increase in intracellular calcium in CD cells. In addition, we observed a dose-dependent increase in cAMP in the CD cells in response to histamine. In short-circuit current studies aimed at measuring sodium reabsorption via the ENaC (epithelial sodium channel expressed in the CD), we observed an inhibition of ENaC-mediated currents by histamine. This was corroborated in immunocytochemistry and qPCR, which showed a decrease in protein and gene expression for the alpha subunit of ENaC upon histamine treatment. To test the functional importance of HRs in kidney physiology and pathophysiology, we used Dahl SS rats, an established model of salt-sensitive hypertension (SSH), which is accompanied with inflammation-driven kidney damage. Ranitidine, an inhibitor of HR2, was administered to these rats, and in vivo studies showed that blocking of this receptor affects renal electrolyte excretion, urine production and water consumption. To sum up, our data highlight the functional importance of HRs in the kidney, and suggest potential implications of histamine in inflammation-related renal diseases, such as SSH. More in-depth research is required to discern the downstream molecular pathways, and assess the role of specific receptors in renal pathophysiology