Histamine N-methyltransferase inhibition attenuates hypertension and proximal tubule damage in Dahl salt-sensitive rats fed a high-salt diet

BACKGROUND: Inflammation is one of the mechanisms of renal disease development in salt-sensitive hypertension (SS-HTN). We have previously shown that Dahl SS rats exhibit higher renal histamine levels when fed a high salt diet and reported that renal epithelium has abundant histaminergic system components. We hypothesized here that inhibition of histamine N-methyltransferase (HNMT) attenuates the development of hypertension and reduces renal damage in the Dahl SS rat. METHODS: Male Dahl SS rats implanted with telemeters were administered HNMT inhibitor SKF-91488 (3.0 mg/kg/day) or vehicle s.c., while fed a 4.0% NaCl high salt diet for 21 days. Renal function and biometric parameters were assessed at endpoint; tissues were collected and subjected to IHC and Western blotting. RESULTS: We report attenuation of hypertension in the SKF-91488 treated group at endpoint (mean arterial pressure = 132.6 ± 11.8 vs. 160.3 ± 6.5 mmHg in control, p < 0.05) and proximal tubule damage measured with KIM-1 (0.8 ± 0.1 vs. 1.7 ± 0.2% stained area fraction, p < 0.01). αSMA IHC of coronary vasculature in the SKF-91488 group demonstrated smaller vessel wall thickness relative to total diameter (p = 0.046). Renal abundance of histamine receptors 1 and 4 (p = 0.01/both) and the pan-macrophage marker CD68 (p = 0.04) were higher in the renal cortex of the SKF-91488 treated group. Urinary Cl- excretion was higher in the SKF-91488 treated rats at endpoint compared to vehicle controls (p < 0.001). CONCLUSIONS: Our study demonstrated that HNMT inhibition alleviates blood pressure and proximal tubule damage in SS-HTN, potentially through immune-related mechanisms.