Obesity-Related Glomerulopathy and Single-Nephron GFR.
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ABSTRACT:
SUBMITTER: Denic A
PROVIDER: S-EPMC7403627 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Obesity-Related Glomerulopathy and Single-Nephron GFR.
Denic Aleksandar A Glassock Richard J RJ
Kidney international reports 20200602 8
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Project description:IntroductionObesity-related glomerulopathy (ORG) is a slowly progressive kidney disease occurring in association with obesity. It is characterized histopathologically by glomerulomegaly, likely caused by single-nephron hyperfiltration that has not been demonstrated in humans because of technical difficulty in measuring single-nephron glomerular filtration rate (SNGFR) in the clinical setting.MethodsTotal glomerular number per kidney, with or without global glomerulosclerosis, was estimated by the combination of cortical volume assessment via unenhanced computed tomography and biopsy-based stereology. Mean glomerular volume was calculated from the measured area of glomerular tufts. Both SNGFR and single-nephron urinary protein excretion (SNUPE) were estimated by dividing values for estimated glomerular filtration rate and urinary protein excretion by the number of nonsclerotic glomeruli. Living kidney donors were used as healthy controls.ResultsA total of 48 ORG patients with average nonsclerotic glomerular numbers of 456,000 ± 235,000 per kidney were included. The values for SNGFR in ORG patients with chronic kidney disease (CKD) stages 1 and 2 were higher than for nonobese and obese controls (97 ± 43 vs. 59 ± 21 vs. 64 ± 21 nl/min, respectively, P = 0.001). Nonsclerotic glomerular number decreased with advancing stages of renal functional impairment. The presence of ORG with more advanced CKD stages was associated with lower SNGFR and marked elevation in SNUPE levels, with no difference in the mean glomerular volume between the stages.ConclusionsThese results provide functional evidence for single-nephron hyperfiltration in patients with ORG, and identify compensatory failure to maintain effective SNGFR as a feature of advanced-stage ORG.
| S-EPMC7403629 | biostudies-literature
Project description: Not available
| S-EPMC10371379 | biostudies-literature
Project description:Obesity-related glomerulopathy (ORG) is a silent comorbidity which is increasing in incidence as the obesity epidemic escalates. ORG is associated with serious health consequences including chronic kidney disease, end-stage renal disease (ESRD), and increased mortality. Although the pathogenic mechanisms involved in the development of ORG are not fully understood, glomerular hemodynamic changes, renin-angiotensin-aldosterone system (RAAS) overactivation, insulin-resistance, inflammation and ectopic lipid accumulation seem to play a major role. Despite albuminuria being commonly used for the non-invasive evaluation of ORG, promising biomarkers of early kidney injury that are emerging, as well as new approaches with proteomics and metabolomics, might permit an earlier diagnosis of this disease. In addition, the assessment of ectopic kidney fat by renal imaging could be a useful tool to detect and evaluate the progression of ORG. Weight loss interventions appear to be effective in ORG, although large-scale trials are needed. RAAS blockade has a renoprotective effect in patients with ORG, but even so, a significant proportion of patients with ORG will eventually progress to ESRD despite therapeutic efforts. It is noteworthy that certain antidiabetic agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be useful in the treatment of ORG through different pleiotropic effects. In this article, we review current approaches and future perspectives in the care and treatment of ORG.
| S-EPMC9286698 | biostudies-literature
Project description:Obesity-related glomerulopathy (ORG) is morphologically defined as focal segmental glomerulosclerosis and glomerulomegaly. Podocyte hypertrophy and reduced density are related to proteinuria which in a portion of patients is in the nephrotic range and evolvs towards renal failure. This article reviews the pathogenetic mechanisms of podocyte injury or dysfunction and lists new possible antiproteinuric strategies based on pharmaceutical targeting of the reported pathogenetic mechanisms. The pathogenetic mechnisms discussed include: renin angiotensin system, plasminogen activation inhibitor-1 (PAI-1), lipid metabolism, adiponectin, macrophages and proinflammatory cytokines, oxidative stress. The proposed antiproteinuric strategies include: AT2 receptor blockers; adipokine complement C19 TNF-related protein-1 blocker; selective PAI-1 inhibitor; farnesoid x receptor activation; increase of circulating adiponectin; selective antiinflammatory drugs; more potent antioxidants (Heme oxigenase, NOX4 inhibitors). However, because ORG is a rare disease, the need for a long term pharmaceutical approach in obese proteinuric patients should be carefully evaluated and limited to the cases with progressive loss of renal function.
| S-EPMC5560488 | biostudies-other
Project description:Obesity, an ongoing significant public health problem, is a part of complex disease characterized as metabolic syndrome. Medaka and zebrafish are useful aquatic experimental animals widely used in the field of toxicology and environmental health sciences and as a human disease models. In medaka, simple feeding of a high fat diet (HFD) can induce body weight gain, excessive accumulation of visceral adipose tissue, hyperglycemia, hyperlipidemia, and steatohepatitis, which mimics human metabolic syndrome. In the present study, to explore the possibility that the adult medaka fed with HFD (HFD-medaka) can be used as an animal model for human metabolic syndrome-associated glomerular disease, including obesity-related glomerulopathy (ORG), we analyzed structural alterations and protein expression in the mesonephric kidney of HFD-medaka. We found that the histopathology was consistent with glomerulomegaly accompanied by the dilation of glomerular capillaries and proliferative expansion of the mesangium, a condition partially comparable to human ORG. Moreover, expressions of several kinds of kidney disease-related proteins (such as MYH9, SM22?) were significantly elevated. Thus, the HFD-medaka has a high potential as an animal model useful for exploring the mechanism underling human ORG.
| S-EPMC3587682 | biostudies-literature
Project description:BackgroundAdolescent obesity, a risk factor for cardiorenal morbidity in adulthood, has reached epidemic proportions. Obesity-related glomerulopathy (ORG) has an early reversible stage of hyperfiltration. Age-appropriate formulae for eGFR, which are standardized to ideal body surface area (BSA) and provide assessment of kidney function in ml/min/1.73 m2, may underestimate prevalence of early ORG. We investigated whether adjusting eGFR to actual BSA more readily identifies early ORG.MethodsWe studied a cohort of 22,417 young individuals, aged 12-21 years, from a New York metropolitan multi-institutional electronic health records clinical database. eGFR was calculated in two ways: BSA-standardized eGFR, and absolute eGFR. Hyperfiltration was defined above a threshold of 135 ml/min per 1.73 m2 or 135 ml/min, respectively. The prevalence of hyperfiltration according to each formula was assessed in parallel to creatinine clearance.ResultsSerum creatinine values and hyperfiltration prevalence according to BSA-standardized eGFR were similar, 13%-15%, across body mass index (BMI) groups. The prevalence of hyperfiltration determined by absolute eGFR differed across BMI groups: underweight, 2%; normal weight, 6%; overweight, 17%; and obese, 31%. This trend paralleled the rise in creatinine clearance across BMI groups.ConclusionsAbsolute eGFR more readily identifies early ORG than the currently used formulae, which are adjusted to a standardized BSA and are not representative of current population BMI measures. Using absolute eGFR in clinical practice and research may improve the ability to identify, intervene, and reverse early ORG, which has great importance with increasing obesity rates.
| S-EPMC8967610 | biostudies-literature
Project description:Obesity-related glomerulopathy (ORG) is an independent risk factor for chronic kidney disease and even progression to end-stage renal disease. Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG, but relatively little is known about cell-specific changes in gene expression. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing. We report for the first time that immune cells, including T cells and B cells, are decreased in ORG patients. Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells. This gene is related to inflammation and cell proliferation. Analysis of differential gene expression in glomerular cells (endothelial cells, mesangial cells, and podocytes) showed that these cell types were mainly enriched in genes related to oxidative phosphorylation, cell adhesion, thermogenesis, and inflammatory pathways (PI3K-Akt signaling, MAPK signaling). Furthermore, we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway. Moreover, an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients, with major interactions between parietal epithelial cells and podocytes. Altogether, our identification of molecular events, cell types, and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.
| S-EPMC10978546 | biostudies-literature
Project description:Obesity-related glomerulopathy is a secondary glomerular disease and its incidence has been increased globally in parallel with the obesity epidemic. ORG emerged as a growing cause of end-stage renal disease in recent years. Unbalanced production of adipokines at the adipose tissue as well as low-grade inflammatory processes play central roles in ORG progression. ORG mouse model with ACE2-knockout was generated and kidney injury was evaluated by biochemistry and histological staining assays. Protein and mRNA expressions were quantified by ELISA, western blot or qRT-PCR methods. ACE2 deficiency aggravated ORG-related renal injuries and stimulated both lipid accumulation and inflammatory responses. Further, Nrf2 pathway was deactivated upon ACE2-knockout. By contrast, ACE2 overexpression reactivated Nrf2 pathway and ameliorated ORG symptoms by decreasing fat deposition and reducing inflammatory responses. Our data demonstrated that ACE2 exerted the beneficial effects by acting through Nrf2 signaling pathway, suggesting the protective role of ACE2 against lipid accumulation and inflammatory responses in ORG pathogenesis.
| S-EPMC9523180 | biostudies-literature
Project description:BackgroundAdiponectin is an adipocytokine that plays a key regulatory role in glucose and lipid metabolism in obesity. The prevalence of obesity has led to an increase in the incidence of obesity-related glomerulopathy (ORG). This study aimed to identify the protective role of adiponectin in ORG.MethodsSmall-interfering RNA (siRNA) against the gene encoding adiponectin was transfected into podocytes. The oxidative stress level was determined using a fluorometric assay. Apoptosis was analyzed by flow cytometry. The expressions of podocyte markers and pyrin domain containing protein 3 (NLRP3) inflammasome-related proteins were measured by qRT-PCR, immunohistochemistry, and Western blot.ResultsPodocytes treated with palmitic acid (PA) showed downregulated expressions of podocyte markers, increased apoptosis, upregulated levels of NLRP3 inflammasome-related proteins, increased production of inflammatory cytokines (IL-18 and IL-1β), and induced activation of NF-κB as compared to the vehicle-treated controls. Decreased adiponectin expression was observed in the serum samples from high fat diet (HFD)-fed mice. Decreased podocin expression and upregulated NLRP3 expression were observed in the kidney samples from high fat diet (HFD)-fed mice. Treatment with adiponectin or the NLRP3 inflammasome inhibitor, MCC950, protected cultured podocytes against podocyte apoptosis and inflammation. Treatment with adiponectin protected mouse kidney tissues against decreased podocin expression and upregulated NLRP3 expression. The knockout of adiponectin gene by siRNA increased ROS production, resulting in the activation of NLRP3 inflammasome and the phosphorylation of NF-κB in podocytes. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, prevented adiponectin from ameliorating FFA-induced podocyte injury and NLRP3 activation.ConclusionsOur study showed that adiponectin ameliorated PA-induced podocyte injury in vitro and HFD-induced injury in vivo via inhibiting the ROS/NF-κB/NLRP3 pathway. These data suggest the potential use of adiponectin for the prevention and treatment of ORG.
| S-EPMC8191043 | biostudies-literature
Project description:Background:The objective of this study was to investigate obesity-related glomerulopathy (ORG) at a cellular, structural and transcriptomic level. Methods:Thirty Wistar rats were randomized into two groups: control rats(n=15), which were fed a standard diet(SD) and study rats(n=15), which were fed a high-fat diet (HFD). After 10 weeks, weight, parameters of kidney function, renal histological features, transcriptomic changes, miRNA and mRNA isolation were compared. Results:HFD gained more weight(55.8%) than SD(29.2%), p<0.001. Albuminuria was also significantly higher in HFD(10,384.04 ng/ml) compared with SD(5,845.45 ng/ml), p<0.001. HFD showed typical lesions of early stages of ORG, with a predominance of mesangial matrix increase (MMI) and podocyte hypertrophy (PH). All histologic lesions correlated with genes differentially expressed (DE) in kidneys of HFD group and PH, also correlated with specific miRNAs DE in the urine of HFD. The functional analysis showed 4 miRNAs DE in the kidneys of HFD group that negatively regulates PTEN gene, which promotes podocyte endocytosis of lipids in ORG. The electronic microscope confirmed the spaces of lipid vacuoles in the podocytes of HFD. Between those 4 miRNAs DE, miR-205 was also found to be upregulated in the urine of HFD group. Conclusions: Wistar rats fed a HFD developed early-stages of ORG, with a specific targetome of miRNAs and gene expression. The upregulation of miR-205 in kidney and its isolation in urine is associated with lipid endocytosis of podocytes, which could become a plausible biomarker of early-stages of ORG and open new avenues for future therapeutics research. Translational Statement: The findings of the basic research in this study can be replicated in human models of obesity. The results of the study on miRNA in humans may contribute to improving the understanding of the pathophysiology of obesity-related glomerulopathy, aiding in the search for early biomarkers, and exploring new therapeutic targets. Keywords: MicroRNA, Biomarker, targetome, obesity-related glomerulopathy, mesangial matrix increase, podocyte hypertrophy, Wistar rats
2024-06-12 | GSE262503 | GEO