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Targeting Fibroblast growth factor-23 (FGF23)-responsive pathways in the control of phosphate and vitamin D metabolism

ABSTRACT: Single cell RNA sequencing (scRNAseq) on wild type (WT) mouse kidneys showed overlapping HBEGF and EGFR expression in the proximal tubule (PT), and KL expression in PT and distal tubule (DT) segments.

ORGANISM(S): Mus musculus

PROVIDER: GSE142113 | GEO | 2019/12/17

REPOSITORIES: GEO

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Targeting Fibroblast growth factor-23 (FGF23) responsive pathways in the control of renal phosphate and vitamin D metabolism

Project description:FGF23 is a bone-derived hormone that mediates renal phosphate reabsorption and 1,25(OH)2 vitamin D metabolism via its required co-receptor alpha-Klotho (KL). The functional pathways guiding this hormone’s activity in kidney have not been studied extensively, and whether using other factors with overlapping signaling profiles to produce FGF23-like responses is unclear. To map FGF23-related genes, gene array and single-cell RNA sequencing were utilized on wild type mouse kidneys. After identifying Heparin-binding EGF-like growth factor (HBEGF) as an up-regulated gene in response to FGF23 delivery, KL-null and phosphate-deficient diet fed mouse models and in vitro experiments were utilized to further test HBEGF bioactivity in kidney. Gene array demonstrated that HBEGF was significantly up-regulated following FGF23 delivery to wild type (WT) mice. Next, mice injected with HBEGF had phenotypes consistent with partial FGF23-mimetic activity including robust induction of EGR1, and increased CYP24A1 mRNAs. Single cell RNA sequencing showed overlapping HBEGF and EGFR expression in the proximal tubule (PT), and KL expression in PT and distal tubule (DT) segments. In KL-null mice devoid of canonical FGF23 signaling, HBEGF injections significantly increased EGR1 and CYP24A, and correction of basally-elevated CYP27B1 was observed. In addition, mice placed on a phosphate deficient diet to suppress FGF23 had endogenously increased CYP27B1 mRNA, which was rescued in mice receiving HBEGF. In HEK293 renal epithelial cells, HBEGF and FGF23 increased CYP24A1 mRNA. Targeting pathways known to be downstream of FGF23 in kidney may help to control renal phosphate handling in diseases of altered FGF23 bioactivity.

2020-10-01 | GSE138992 | GEO

PPARs and c-Myc regulate metabolism of renal tubules

Project description:Different segments of renal tubules have distinct metabolic features and functions, and defective metabolism in renal tubules is involved in the pathobiology of kidney diseases. However, the mechanisms underlying the metabolic regulation in renal tubules remain to be defined. We demonstrated that the renal proximal tubule (PT) has high expression of fatty acid and lipid metabolism enzymes, which is transcriptionally upregulated by abundantly expressed peroxisome proliferator-activated receptor (PPAR)/γ to support active lipid metabolism. In contrast, the renal distal tubule (DT) has elevated glycolytic enzyme expression corresponding with high rates of glycolysis, and this increased expression is mediated by abundantly expressed c-Myc. In addition, Nrf2 upregulated glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and NADP-dependent malic enzyme 1 expression for NADPH production and antioxidation in the DT. Highly expressed PPARγ transcriptionally enhanced expression of the protease iRhom2 in the PT, which suppressed epidermal growth factor (EGF) expression and secretion, inhibiting EGF receptor activation-dependent glycolytic gene expression and maintaining the low level of glycolysis. PPARγ inhibition reduced iRhom2 expression and increased EGF and GLUT1 expression in the PT in mice, resulting in hypertrophy of renal tubules and inhibited kidney functions, which can be rescued by inhibition of glycolysis via treatment with 2-deoxy-D-glucose. These findings delineate instrumental molecular mechanisms underlying the active lipid metabolism and suppressed glycolysis in the PT and active glycolysis in the DT and reveal critical roles for PPARs and c-Myc in maintaining metabolic homeostasis in the kidney

2018-11-15 | PXD007828 | Pride

Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids

Project description:Improved specification of metanephric nephron progenitors in conditions that prolong differentiation while simultaneously preventing spontaneous nephron induction resulted in proximal tubule (PT)-enhanced kidney organoids. PT-enhanced organoids exhibited improved PT maturation, with elongated and aligned nephron segments as well as distinct loops of Henle. The striking proximo-distal orientation of nephrons was shown to result from localised WNT antagonism originating from the centre of the organoid.

2022-08-25 | GSE184928 | GEO

Proximal tubular transcriptional response to aristolochic acid

Project description:The proximal tubule is particularly susceptible to acute kidney injury caused by ischemic or toxic insults, due to its high oxygen demand, and role in excreting drugs such as DNA-damaging chemotherapeutics. AKI triggers PT cell de-differentiation, expression or pro-inflammatory and pro-fibrotic signaling molecules, and a dramatic shift in PT cell metabolism with severe suppression of fatty acid oxidation. The aim of this study was to investigate the transcriptional changes that occur in the S2 and S3 segments of the PT in response to the DNA damaging agent aristolochic acid I (AAI).

2021-05-18 | GSE150897 | GEO

Proteomic analysis of murine kidney proximal tubule sub-segment derived cell lines reveals preferences in mitochondrial pathway activity

Project description:The proximal tubule (PT) is a highly energetic segment of the nephron, responsible for the majority of solute and water reabsorption in the kidney. Each of its sub-segments have specialized functions; however, little is known about the genes and proteins that determine the oxidative phosphorylation capacity of the PT sub-segments. This information is a critical deficit in understanding kidney function and to develop a fuller comprehensive landscape of renal cell adaptations to injury, toxins, physiologic stressors, and development. In this study, three immortalized murine renal cell lines (PT S1,S2 and S3 segments) were analyzed for protein content and compared to a murine fibroblast cell line. All three proximal tubule cell lines generate ATP predominantly by oxidative phosphorylation while the fibroblast cell line is glycolytic. The proteomic data demonstrates that the most striking difference in proteomic signatures between the cell lines are differences in nuclear proteins followed by differences in mitochondria proteome. The mitochondria physiologic profile is also determined in the cell lines to provide physiologic context to the proteomic dataset. This data set will allow researchers to study differences in nephron-specific cell lines, differences between epithelial and fibroblast cells, and differences between actively respiring cells and glycolytic cells.

2022-07-07 | MSV000089838 | MassIVE

Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23.

Project description: Not available

| S-EPMC4777331 | biostudies-literature

Role of the vitamin D receptor in FGF23 action on phosphate metabolism.

Project description: Not available

| S-EPMC1184586 | biostudies-other

RNA-seq profiling of microdissected rat renal tubule segments

Project description:We sequenced mRNAs from glomeruli and 14 different rat renal tubule segments collected by hand microdissection. Collagenase-digested rat renal tubule segments were collected by hand microdissection. Poly(A)-mRNAs were captured from cell lysate and sequenced using paired-end protocol.

2015-03-31 | E-GEOD-56743 | biostudies-arrayexpress

The changes of Chromatin Accessibiliy Triggered by Unilateral Nephrectomy [ATAC-seq]

Project description:Purpose: Experiments were done in mice undergoing unilateral nephrectomy (UNx) and sham nephrectomy. At specific time points (24 hours and 72 hours) after surgery, the earliest first portion of the kidney proximal tubule (PT-S1) and the cortical collecting duct (CCD) were manually micro-dissected and utilized for transcriptomic analysis by single-tubule small sample RNA-Seq and single-tubule ATAC seq. Methods: We carried out ATAC-sequencing in microdissected ealiest portion of proximal tubules (PT-S1) from mice with or without (sham) unilateral nephrectomy (UNx). Each group (Sham or UNx) has 3 biological replicates. Results and conclusion: ATAC-seq peaks in microdissected PT-S1 revealed a predominance of binding site motifs corresponding to PPARα.

2022-08-14 | GSE211022 | GEO

Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism.

Project description: Not available

| S-EPMC4489419 | biostudies-literature