FBLN2 Abates Epigenetic-mediated Salt-sensitive Hypertension Through Regulation of NCC Trafficking

Abstract

Epigenetics play a role in the development of hypertension. However, the precise mechanisms of how histone modification in renal tubule cells regulates blood pressure is largely undiscovered. In this study, we investigated the role of renal Kdm6a in salt-sensitive hypertension using a kidney tubular cell-specific Kdm6a gene knockout (Kdm6a cKO) mouse model. First, we demonstrated that knockout of Kdm6a in the renal tubular cells resulted in an increase of H3K27me3 associated with the development of hypertension in both male and female Kdm6a cKO mice. To explore the mechanism of H3K27me3-mediated hypertension, we performed a ChIP seq to identify the target genes of H3K27me3 in the renal tubular cells. Data showed that H3K27me3 regulated several physiological pathways in the renal tubular cells, including sodium transport in proximal convoluted tubule (PCT), and blood pressure regulation in distal convoluted tubule (DCT). Indeed, we found that the expressions of NCC, NKCC2, and AQP2 were upregulated in kidneys of Kdm6a cKO mice. Furthermore, ChIP seq data reveals that FBLN2, an extracellular matrix protein, appears to be a target of H3K27me3, which was downregulated in the kidney of Kdm6a cKO mice determined by real-time PCR, Western, and IHC. Notably, we demonstrated that FBLN2 abated high salt-induced hypertension through downregulation of NCC, NKCC2, and AQP2 in the tubular cells of Kdm6a cKO mice. Interestingly, pre-treatment of FBLN2 prevented salt-sensitive hypertension in these mice. Additionally, we have provided evidence that FBLN2 may regulate blood pressure through mediating the NCC cell membrane trafficking. Using a super high-resolution microscopy, we demonstrated that FBLN2 reduced levels of cell surface NCC in DCT cells cultured in hypotonic medium. Here, we have first demonstrated that FBLN2 may be a target gene of H3K27me3 in epigenetic-mediated hypertension. FBLN2 treatment may prevent and treat salt-sensitive hypertension. NIH This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.