CD36 Gates Nocturnal Hypertension via the Renal AMPK/HDAC5/PER1 Axis

Nocturnal hypertension is a strong predictor of cardio-cerebrovascular disease, yet its underlying mechanisms remain largely unknown. In this study, we identified CD36 as a key regulator of blood pressure (BP) rhythms and as a gatekeeper of nocturnal hypertension. Its deficiency disrupts circadian BP rhythms.

We continuously monitored 48-hour BP using telemetry in CD36 global knockout mice and renal proximal tubule-specific CD36 knockout mice. We also collected serum samples and ambulatory BP monitoring data from patients with nocturnal hypertension to assess the relationship between CD36 expression and nocturnal hypertension. A comprehensive screening of various factors affecting BP and circadian rhythms was conducted to explore the molecular mechanisms.

Our telemetry data revealed significantly elevated BP during the daytime (inactive period) in both CD36 global knockout and renal proximal tubule-specific knockout mice compared with their control counterparts. Furthermore, levels of platelet CD36 were negatively correlated with the severity of nocturnal hypertension in humans. Mechanistically, CD36 modulates BP rhythms through the AMPK (AMP-activated protein kinase)/HDAC5 (histone deacetylase 5)/PER1 pathway: its deficiency activates phosphorylated AMPK, leading to the dissociation of the HDAC5-PER1 complex, enhancing PER1 nuclear accumulation, and desynchronizing the oscillations of intrarenal renin-angiotensin-aldosterone system genes and clock-controlled genes, ultimately disrupting BP rhythm.

Our findings highlight CD36 as a critical integrator that links renal clocks to BP homeostasis, establishing it as a potential predictor and therapeutic target for nocturnal hypertension.