Introduction: The molecular clock plays an essential role in regulating cardiovascular function and immune responses through rhythmic expression of clock-controlled transcripts and their biological functions. Our previous study showed that myeloid-specific deletion of Bmal1 promotes atherosclerosis in ApoE-/- mice by enhancing monocyte trafficking to plaques. The role of Bmal1 in renal and vascular inflammation in hypertension is unknown.
Hypothesis: We propose that Bmal1 contributes to renal interstitial inflammation and immune cell infiltration in the kidney thus accelerates renal dysfunction and hypertension; while also promotes vascular inflammation and dysfunction.
Methods: We use the Bmal1FloxP/FloxP (Bmal1MWT) as control and Bmal1FloxP/FloxP;LysMCre/+ (Bmal1MKO) as myeloid-specific Bmal1-deficient mice housed under 12 hour light/dark cycle at 22°C. Hypertension was induced by angiotensin II infusion via osmotic pump for 28 days. Kidney was enzymatically digested to single cell suspension for flow cytometric analysis. Vascular reactivity was measured using myograph.
Results and Conclusions: We found higher systolic (131.5±7.2 vs 117.8±9.7mmHg) and albumin-to-creatinine ratio in Bmal1MKO compared to Bmal1MWT mice after angiotensin II infusion. Flow cytometric analysis showed more total macrophages (CD11b+F4/80+) and more Ly6c+ macrophages in the kidney from Bmal1MKO mice. There were also more CD11b+ dendritic cells (CD11c+MHCII+), but not CD103+ DCs in the kidney, indicating Bmal1 deficiency promotes monocyte trafficking and infiltration into the kidney and differentiation into macrophages and DCs in hypertensive mice. Immunostaining showed more macrophages and DCs in the interstitial area of kidney from Bmal1MKO mice. Besides, endothelium-dependent vasodilation in mesenteric arteries was further impaired in hypertensive Bmal1MKO mice, indicating Bmal1 deletion promotes hypertension-induced vascular dysfunction. Our results indicate myeloid Bmal1 deletion exacerbates hypertension and hypertension-induced renal and vascular inflammation. Further experiments using CCL2 and CX3CL1 antibodies are carried out to examine the significant role of monocyte infiltration.