ABSTRACT
Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.
Subject(s)
Energy Metabolism , Polycystic Kidney, Autosomal Dominant , Systems Biology , Humans , Systems Biology/methods , Polycystic Kidney, Autosomal Dominant/metabolism , Polycystic Kidney, Autosomal Dominant/genetics , TRPP Cation Channels/metabolism , TRPP Cation Channels/genetics , Mitochondria/metabolism , Mitochondria/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Oxidative Phosphorylation , Gene Expression RegulationABSTRACT
Polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of Polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been recently implicated in cystogenesis, and we identified the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway as an emerging mediator of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF is activated by PC1/2 loss and plays a critical role in the fibrogenic reprogramming of the epithelium. The loss of PC1 or PC2, induced by siRNA in vitro, activated RhoA and caused cytoskeletal remodeling and robust nuclear MRTF translocation and overexpression. These phenomena were also manifested in PKD1 (RC/RC) and PKD2 (WS25/-) mice, with MRTF translocation and overexpression occurring predominantly in dilated tubules and the cyst-lining epithelium, respectively. In epithelial cells, a large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for the paracrine priming of the fibroblast-myofibroblast transition. Thus, MRTF acts as a prime inducer of epithelial fibrogenesis in PKD. We propose that RhoA is a common upstream inducer of both histological hallmarks of PKD: cystogenesis and fibrosis.
Subject(s)
Epithelial Cells , Polycystic Kidney Diseases , TRPP Cation Channels , rhoA GTP-Binding Protein , Animals , Humans , Mice , Cytoskeleton/metabolism , Epithelial Cells/metabolism , Epithelial Cells/pathology , Fibrosis , Mice, Inbred C57BL , Polycystic Kidney Diseases/metabolism , Polycystic Kidney Diseases/pathology , Polycystic Kidney Diseases/genetics , rhoA GTP-Binding Protein/metabolism , Trans-Activators/metabolism , TRPP Cation Channels/metabolism , TRPP Cation Channels/geneticsABSTRACT
Magnesium hydroxide (Mg(OH)2), as a green halogen-free flame retardant, has attracted significant attention in the field of flame retardant composite materials. In addition to conventional indicators such as purity and whiteness, Mg(OH)2 is required to take the form of regular hexagonal sheets to ensure the dispersion of composite materials. We use irregular large particles of Mg(OH)2 prepared by the magnesium factory in western Qinghai as raw materials to study the influence of alkali metal ions K+ and Na+ mainly present in salt lakes on the physicochemical properties of Mg(OH)2. The products were characterized via X-ray diffraction, scanning electron microscopy, automatic nitrogen physical adsorption apparatus, and other modern characterization techniques. Results show that alkali metal ions K+ and Na+ considerably influence the crystal surface polarity, particle size, and morphology of the prepared Mg(OH)2. The mechanism analysis shows that the presence of K+ and Na+ alters the dissolution, recrystallization, and growth characteristics of Mg(OH)2. This study provides theoretical support for the realization of high-performance Mg(OH)2 using salt lake resources and demonstrates the value for promoting the large-scale industrial application of the salt lake industry.