Physiological effects of histamine on renal function in salt‐sensitive hypertension

Abstract

Introduction . Histamine is a regulatory agent involved in the immune response, neurotransmission, and gastric acid secretion, and is produced and released from the mast cells and basophils. Elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in kidney diseases. The goal of this study is to provide insight into the physiological importance of the histamine-related pathways in salt-sensitive hypertension (SSH), a disease accompanied with inflammation-driven kidney damage. Methods . SSH was induced in Dahl Salt-Sensitive (DSS) rats by a 3-week long high salt diet challenge (HS, 4% NaCl); age-matched normal salt diet (NS, 0.4% NaCl) fed rats were used as a control group. To characterize the expression of histamine receptors, mast cells markers, and histamine metabolism-related enzymes, Western blot or IHC were performed on renal tissues collected from DSS rats maintained on HS or NS diets for 3 weeks. In order to test the effects of histamine receptor 2 (HR2) inhibition, he DSS rats were injected with a single daily i.p. dose of an HR2 blocker, ranitidine (RAN, 25mg/kg in saline) or saline (VEH), for 3 consecutive days before the switch to a HS diet, and at the end of the 21-day long HS challenge. Urine and water consumption were assessed in metabolic cages during hours 0-8 (acute), and 8-24 post-injections. At the end of the protocol, GFR was measured, and tissues were harvested. Results . Western blots revealed similar expression of the mast cell markers’ (FCER1A and tryptase) in NS and HS diet fed rats, however, we observed significantly lower histamine decarboxylase (HDC, p=0.002), and higher histamine N-methyltransferase (HNMT, p=0.035) levels in HS diet fed rats. Renal IHC revealed that expression of HR2 was downregulated, while HR3 and HR4 were upregulated in the collecting ducts of HS diet fed rats. In vivo experiments showed that RAN-administered rats on NS diet exhibited an acute (8-24 hr period) decrease in urine output and 24 h water intake on day 1 of injections (p=0.01). We observed trends for an increase in urinary electrolytes, and an overall increase in the excretion of osmolesin RAN vs VEH animals 24 hours post day 1 injection on the NS diet. Post HS challenge, electrolyte excretion, urine flow and water intake were similar between RAN and VEH animals. At the endpoint on HS, GFR between the groups was similar on day 3 post-injection. Conclusions . Differential expression of HRs, as well as changes in the enzymes responsible for histamine synthesis and metabolism between HS and NS fed rats, indicate a shift in the renal histaminergic tone during SSH development. Similar mast cell levels suggest an alternate, perhaps intrarenal, source of histamine. Our in vivo data show that inhibition of HR2 has effects on urine output and water consumption in SSH. Further research is required to discern the molecular pathways downstream of specific HRs, as well as the consequences of chronic administration of HR-specific pharmacology, in renal pathophysiology.