Renal histaminergic system and acute effects of histamine receptor 2 blockade on renal damage in the Dahl salt-sensitive rat

Abstract

Histamine is involved in the immune response, vasodilation, neurotransmission, and gastric acid secretion. Although elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in renal disease, there is gap in knowledge regarding the mechanisms of histamine-related pathways in the kidney. We report here that all four histamine receptors, as well as enzymes responsible for metabolism of histamine are expressed in human and rat kidney tissues. In this study, we hypothesized that the histaminergic system plays a role in salt-induced kidney damage in Dahl Salt-Sensitive (DSS) rat, a model characterized with inflammation-driven renal lesions. To induce renal damage related to salt-sensitivity, DSS rats were challenged with a 21 days of high salt diet (HS, 4% NaCl); normal salt diet (NS, 0.4% NaCl) fed rats were used as a control. We observed lower histamine decarboxylase (HDC), and higher histamine N-methyltransferase (HNMT) levels in HS diet-fed rats, indicative of a shift in the histaminergic tone; metabolomics showed higher histamine and histidine levels in the kidneys HS diet-fed rats, while plasma levels for both compounds were lower. Acute systemic inhibition of histamine receptor 2 (HR2) in the DSS rat revealed that it lowered vasopressin receptor 2 and AQP2 abundance in the kidney. In summary, we established here the existence of the local histaminergic system, revealed a shift in the renal histamine balance during salt-induced kidney damage, and provided evidence that blockage of HR2 in the DSS rat affects water balance and urine concentrating mechanisms.