SIRT1/NRF2 axis regulates NLRP3-mediated macrophage inflammation and renal injury in hypertension with hyperuricemia.

BACKGROUND

Hypertension and hyperuricemia commonly coexist and are associated with persistent inflammation and renal injury. However, the mechanism linking these two conditions remains unclear. This study investigated whether the SIRT1/NRF2 axis regulates NLRP3-mediated macrophage inflammation in hypertension complicated by hyperuricemia.

METHODS

Clinical data from 84 patients with hypertension and hyperuricemia and 84 patients with hypertension alone were analyzed. Circulating NLRP3 and inflammatory cytokines were measured, and the value of NLRP3 in identifying hyperuricemia occurrence and predicting 6-month recurrence was evaluated. In parallel, a rat model of hypertension with hyperuricemia was established using spontaneously hypertensive rats treated with potassium oxonate. NLRP3 activation or inhibition was induced with QS-21 or MCC950, respectively, and the SIRT1 inhibitor EX527 was used to inhibit SIRT1 activity and affect downstream NRF2 signaling. Renal histopathology, oxidative stress, pyroptosis, macrophage polarization, and pathway-related proteins were assessed.

RESULTS

Circulating NLRP3, IL-1β, TNF-α, IL-18, BUN, Cr, and UA were higher in patients with hypertension and hyperuricemia than in those with hypertension alone. NLRP3 was positively correlated with inflammatory and renal function markers and showed an association with HUA occurrence and 6-month recurrence. However, its diagnostic and prognostic performance was moderate, particularly with regard to sensitivity for recurrence, suggesting that circulating NLRP3 should be interpreted as an exploratory inflammatory marker rather than a standalone clinical biomarker. In rats, NLRP3 activation aggravated renal damage, pyroptosis, M1 macrophage polarization, and ROS-associated oxidative injury, whereas NLRP3 inhibition attenuated these changes. SIRT1 and NRF2 expression was reduced in the model group, and EX527 further enhanced NLRP3 expression and inflammatory injury. The protective effect of MCC950 was largely lost after combined EX527 treatment.

CONCLUSIONS

Suppression of the SIRT1/NRF2 pathway is associated with NLRP3 activation, macrophage inflammatory polarization, and renal injury in hypertension complicated by hyperuricemia. The SIRT1/NRF2-NLRP3 axis may represent a potential target for mechanistic evaluation and therapeutic intervention.