Fibulin 2 Deficiency Drives Epigenetic Hypertension

Although epigenetic modification of histone in embryonic development is well documented, its mechanistic role in the pathogenesis of hypertension is poorly understood. The purpose of this study is to investigate how histone 3 modification (H3K27me3 [trimethylation of histone 3 lysine 27]) in renal tubule cells regulates sodium excretion and blood pressure.

A mouse model of inducible renal tubule cell-specific deletion of KDM6A cKO (histone 3 lysine 27 demethylase 6A gene) was generated.

Here, we uncovered the potential role of FBLN2 (fibulin 2) in the pathogenesis of epigenetic hypertension due to KDM6A cKO. KDM6A is a specific demethylase for H3K27me3. ChIP-seq analysis revealed that the H3K27me3 mark was increased in the promoter region of the FBLN2 gene, resulting in downregulation of FBLN2 protein expression in the kidney of KDM6A cKO mice. Treatment with rFBLN2 (recombinant FBLN2) largely attenuated blood pressure elevation, rescued impairment in sodium excretion, and prevented high salt-induced salt-sensitive hypertension in KDM6A cKO mice. Mechanistically, treatment with rFBLN2 rescued upregulation of NCC (Na-Cl cotransporter) and AQP2 (aquaporin 2) expression and decreased NKCC2 expression in renal tubular cells in the KDM6A cKO hypertensive mice. Intriguingly, FBLN2 may regulate NCC trafficking via forming an FBLN2/NCC complex, which decreases the cell membrane abundance of NCC by translocating NCC to the total membrane in distal convoluted tubule cells.

These findings highlight a critical role of FBLN2 in the regulation of renal sodium excretion and blood pressure and suggest that FBLN2 deficiency may drive KDM6A deficiency-induced epigenetic hypertension. FBLN2 treatment may provide a new preventive and therapeutic strategy for salt-sensitive hypertension.