👤 Daniel L Galvan

Recent studies have highlighted the deleterious role of high phosphate intake in hypertension via sympathetic overactivation, yet the underlying mechanisms remain unclear. Dietary phosphate loading triggers physiologic release of FGF23 (fibroblast growth factor-23) from the bone to maintain phosphate homeostasis. Both FGF23 and FGF receptors (FGFRs) are present in the central nervous system, but their role in neural control of blood pressure during phosphate loading is unknown. We investigated central FGF23/FGFR signaling in high-phosphate diet-induced sympathetic dysregulation of blood pressure in rats. FGF23 protein levels were measured by immunoprecipitation, immunoblotting, and immunohistochemistry. FGF23 translocation into the brain was determined by injecting infrared-labeled FGF23 intravenously into anesthetized Sprague-Dawley rats. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction were measured in decerebrate Sprague-Dawley rats treated with either a normal 0.6% phosphate diet (NP) or a high 1.2% phosphate diet (HP) for 12 weeks before and after intracerebroventricular (ICV) administration of FGFR signaling inhibitors. Excess phosphate intake significantly increased FGF23 protein levels in the brainstem (HP versus NP, Our data reveal a novel pathophysiologic paradigm of high-phosphate diet-induced sympathoexcitation and hypertension by FGF23 crossing into the brain, possibly acting via FGFR4. Show less

Long noncoding RNAs (lncRNAs) have been shown to play key roles in a variety of biological activities of the cell. However, less is known about how lncRNAs respond to environmental cues and what transcriptional mechanisms regulate their expression. Studies from our laboratory have shown that the lncRNA Tug1 (taurine upregulated gene 1) is crucial for the progression of diabetic kidney disease, a major microvascular complication of diabetes. Using a combination of proximity labeling with the engineered soybean ascorbate peroxidase (APEX2), ChIP-qPCR, biotin-labeled oligonucleotide pulldown, and classical promoter luciferase assays in kidney podocytes, we extend our initial observations in the current study and now provide a detailed analysis on a how high-glucose milieu downregulates Tug1 expression in podocytes. Our results revealed an essential role for the transcription factor carbohydrate response element binding protein (ChREBP) in controlling Tug1 transcription in the podocytes in response to increased glucose levels. Along with ChREBP, other coregulators, including MAX dimerization protein (MLX), MAX dimerization protein 1 (MXD1), and histone deacetylase 1 (HDAC1), were enriched at the Show less