American journal of hypertension · 2026
Histamine N-methyltransferase inhibition attenuates hypertension and proximal tubule damage in Dahl SS rats fed a high salt diet.
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Chaudhuri Antara, Andrews Corey E, Cherezova Alena, Spires Denisha R, Zamaro Alexandra S, Reyes Monroy Karen A, Christopher Courtney J, Jones Adam C, Wade Ray M, Verbeck Guido, Campagna Shawn R, Faulkner Jessica L, Palygin Oleg, Ilatovskaya Daria V
Аннотация
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.
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.