Abstract:Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, a… Show more
“…We used our miRNA profiling results to explore mirPath 149 and identified many additional T1D- and renal fibrosis–associated pathways, including the regulation of focal and cell adhesion molecules, tight/gap/adherens junctions, and ECM-receptor interactions, among many more ( Figure 6 ). 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 Figure 6 Identification of pathways associated with microRNAs (miRNAs) from patients with type 1 diabetes (T1D). Seventy-seven miRNAs from patients with T1D who showed differential concentration changes in extracellular vesicles was run through the mirPath program ( http://diana.imis.athena-innovation.gr/DianaTools/index.php?r=mirpath ) to identify predicted targeted pathways.…”
IntroductionDiabetic nephropathy (DN) is a form of progressive kidney disease that often leads to end-stage renal disease (ESRD). It is initiated by microvascular complications due to diabetes. Although microalbuminuria (MA) is the earliest clinical indication of DN among patients with type 1 diabetes (T1D), it lacks the sensitivity and specificity to detect the early onset of DN. Recently, microRNAs (miRNAs) have emerged as critical regulators in diabetes as well as various forms of kidney disease, including renal fibrosis, acute kidney injury, and progressive kidney disease. Additionally, circulating extracellular miRNAs, especially miRNAs packaged in extracellular vesicles (EVs), have garnered significant attention as potential noninvasive biomarkers for various diseases and health conditions.MethodsAs part of the University of Pittsburgh Epidemiology of Diabetes Complications (EDC) study, urine was collected from individuals with T1D with various grades of DN or MA (normal, overt, intermittent, and persistent) over a decade at prespecified intervals. We isolated EVs from urine and analyzed the small-RNA using NextGen sequencing.ResultsWe identified a set of miRNAs that are enriched in urinary EVs compared with EV-depleted samples, and identified a number of miRNAs showing concentration changes associated with DN occurrence, MA status, and other variables, such as hemoglobin A1c levels.ConclusionMany of the miRNAs associated with DN occurrence or MA status directly target pathways associated with renal fibrosis (including transforming growth factor-β and phosphatase and tensin homolog), which is one of the major contributors to the pathology of DN. These miRNAs are potential biomarkers for DN and MA.
“…We used our miRNA profiling results to explore mirPath 149 and identified many additional T1D- and renal fibrosis–associated pathways, including the regulation of focal and cell adhesion molecules, tight/gap/adherens junctions, and ECM-receptor interactions, among many more ( Figure 6 ). 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 Figure 6 Identification of pathways associated with microRNAs (miRNAs) from patients with type 1 diabetes (T1D). Seventy-seven miRNAs from patients with T1D who showed differential concentration changes in extracellular vesicles was run through the mirPath program ( http://diana.imis.athena-innovation.gr/DianaTools/index.php?r=mirpath ) to identify predicted targeted pathways.…”
IntroductionDiabetic nephropathy (DN) is a form of progressive kidney disease that often leads to end-stage renal disease (ESRD). It is initiated by microvascular complications due to diabetes. Although microalbuminuria (MA) is the earliest clinical indication of DN among patients with type 1 diabetes (T1D), it lacks the sensitivity and specificity to detect the early onset of DN. Recently, microRNAs (miRNAs) have emerged as critical regulators in diabetes as well as various forms of kidney disease, including renal fibrosis, acute kidney injury, and progressive kidney disease. Additionally, circulating extracellular miRNAs, especially miRNAs packaged in extracellular vesicles (EVs), have garnered significant attention as potential noninvasive biomarkers for various diseases and health conditions.MethodsAs part of the University of Pittsburgh Epidemiology of Diabetes Complications (EDC) study, urine was collected from individuals with T1D with various grades of DN or MA (normal, overt, intermittent, and persistent) over a decade at prespecified intervals. We isolated EVs from urine and analyzed the small-RNA using NextGen sequencing.ResultsWe identified a set of miRNAs that are enriched in urinary EVs compared with EV-depleted samples, and identified a number of miRNAs showing concentration changes associated with DN occurrence, MA status, and other variables, such as hemoglobin A1c levels.ConclusionMany of the miRNAs associated with DN occurrence or MA status directly target pathways associated with renal fibrosis (including transforming growth factor-β and phosphatase and tensin homolog), which is one of the major contributors to the pathology of DN. These miRNAs are potential biomarkers for DN and MA.
“…In mammals, EGFR signaling is broadly implicated in renal fibrosis (47), and these effects may be modulated in part by GPCR crosstalk (48). MAPK/ERK modulates TGF-β1 and its transcription factor Smad2/3, which potently induces collagen transcription in fibrosis (49). Future work can resolve whether aldosterone and ecdysone in Drosophila uses dopEcR to license the ability of dEGFR to stimulate pericardin.…”
Aldosterone is produced by the mammalian adrenal cortex to modulate blood pressure and fluid balance, however excessive, prolonged aldosterone production promotes fibrosis and kidney failure. How aldosterone triggers disease may involve actions that are independent of its canonical mineralocorticoid receptor. Here we present a Drosophila model of renal pathology caused by excess extra-cellular matrix formation, stimulated by exogenous aldosterone and insect ecdysone steroids. Chronic administration of aldosterone or ecdysone induces expression and accumulation of collagen-like pericardin at adult nephrocytes -podocyte-like cells that filter circulating hemolymph. Excess pericardin deposition disrupts nephrocyte (glomerular) filtration and causes proteinuria in Drosophila, hallmarks of mammalian kidney failure. Steroid-induced pericardin arises from cardiomyocytes associated with nephrocytes, reflecting an analogous role of mammalian myofibroblasts in fibrotic disease. Remarkably, the canonical ecdysteroid nuclear hormone receptor, ecdysone receptor EcR, is not required for aldosterone or ecdysone to stimulate pericardin production or associated renal pathology.Instead, these hormones require a cardiomyocyte-associated G-protein coupled receptor, dopamine-EcR (dopEcR), a membrane-associated receptor previously characterized in the fly brain as affecting behavior. This Drosophila renal disease model reveals a novel signaling pathway through which steroids may potentially modulate human fibrosis through proposed orthologs of dopEcR.
Significance Statement (120)Aldosterone regulates salt and fluid homeostasis, yet excess aldosterone contributes to renal fibrosis. Aldosterone acts through a nuclear hormone receptor, but an elusive, G-protein coupled receptor (GPCR) is thought to also mediate the hormone's pathology. Here we introduce a Drosophila model of renal fibrosis. Flies treated with human aldosterone produce excess extra-cellular matrix and that causes kidney pathology. Flies treated with the insect steroid ecdysone produce similar pathology, and from this analogous response we identify an alternative receptor through which steroids mediate renal fibrosis --the GPCR dopamine-Ecdysone Receptor (dopEcR). dopEcR functions in heart muscle cells associated with nephrocytes, analogous to the role of myofibroblasts in human fibrosis. This finding opens avenues to identify mammalian GPCR homologs of dopEcR through which aldosterone mediates renal fibrosis. which receptor aside from MR might aldosterone stimulate G-coupled signaling and how does this modulate fibrosis?Here we address these issues with a new model of steroid-induced fibrosis based on Drosophila melanogaster. Genetic data reveal the GPRC dopamine-EcR (dopEcR) is necessary and sufficient for aldosterone and insect ecdysone to induce excess extra cellular matrix at nephrocytes and to disrupt fly renal function. Based on our findings we propose that mammalian homologs of dopEcR may offer a novel entrée to moderate fibrotic pathology in humans.
ResultsThe tub...
“…Endophilin-A1 is required for endocytosis, which controls internalization of micronutrients and turnover of membrane components 37 . The relationship between endophilin-A1 and renal disease comes from the role of this protein in uptake of several receptor tyrosine kinases including EGFR, VEGFR, PDGFR, and IGF-1R 37 , which play a key role in renal fibrosis 38,39 .…”
Omics data integration and systems biology analysis on the level of interaction networks provide a powerful approach for identification of pathway-specific biomarkers for MN.
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