The protective effect of human renal sinus fat on glomerular cells is reversed by the hepatokine fetuin-A.
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ABSTRACT:
SUBMITTER: Wagner R
PROVIDER: S-EPMC5442123 | biostudies-literature | 2017 May
REPOSITORIES: biostudies-literature
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The protective effect of human renal sinus fat on glomerular cells is reversed by the hepatokine fetuin-A.
Wagner R R Machann J J Guthoff M M Nawroth P P PP Nadalin S S Saleem M A MA Heyne N N Königsrainer A A Fend F F Schick F F Fritsche A A Stefan N N Häring H-U HU Schleicher E E Siegel-Axel D I DI
Scientific reports 20170523 1
Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of pro ...[more]
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Project description:Aims/hypothesisNeonatal beta cells carry out a programme of postnatal functional maturation to achieve full glucose responsiveness. A partial loss of the mature phenotype of adult beta cells may contribute to a reduction of functional beta cell mass and accelerate the onset of type 2 diabetes. We previously found that fetuin-A, a hepatokine increasingly secreted by the fatty liver and a determinant of type 2 diabetes, inhibits glucose-stimulated insulin secretion (GSIS) of human islets. Since fetuin-A is a ubiquitous fetal glycoprotein that declines peripartum, we examined here whether fetuin-A interferes with the functional maturity of beta cells.MethodsThe effects of fetuin-A were assessed during in vitro maturation of porcine neonatal islet cell clusters (NICCs) and in adult human islets. Expression alterations were examined via microarray, RNA sequencing and reverse transcription quantitative real-time PCR (qRT-PCR), proteins were analysed by western blotting and immunostaining, and insulin secretion was quantified in static incubations.ResultsNICC maturation was accompanied by the gain of glucose-responsive insulin secretion (twofold stimulation), backed up by mRNA upregulation of genes governing beta cell identity and function, such as NEUROD1, UCN3, ABCC8 and CASR (Log2 fold change [Log2FC] > 1.6). An active TGFβ receptor (TGFBR)-SMAD2/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed ALDOB, a gene disallowed in mature beta cells. In fetuin-A-treated NICCs, upregulation of beta cell markers and the onset of glucose responsiveness were suppressed. Concomitantly, SMAD2/3 phosphorylation was inhibited. Transcriptome analysis confirmed inhibitory effects of fetuin-A and SB431542 on TGFβ-1- and SMAD2/3-regulated transcription. However, contrary to SB431542 and regardless of cMYC upregulation, fetuin-A inhibited beta cell proliferation (0.27 ± 0.08% vs 1.0 ± 0.1% Ki67-positive cells in control NICCs). This effect was sustained by reduced expression (Log2FC ≤ -2.4) of FOXM1, CENPA, CDK1 or TOP2A. In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4 ± 1.2% and 22.3 ± 1.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8 mmol/l glucose in control- and fetuin-A-cultured islets, respectively. In addition, fetuin-A reduced SMAD2/3 phosphorylation and suppressed expression of proliferative genes. Of note, in non-diabetic humans, plasma fetuin-A was negatively correlated (p = 0.013) with islet beta cell area.Conclusions/interpretationOur results suggest that the perinatal decline of fetuin-A relieves TGFBR signalling in islets, a process that facilitates functional maturation of neonatal beta cells. Functional maturity remains revocable in later life, and the occurrence of a metabolically unhealthy milieu, such as liver steatosis and elevated plasma fetuin-A, can impair both function and adaptive proliferation of beta cells.Data availabilityThe RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144950.
| S-EPMC8099843 | biostudies-literature
Project description:OBJECTIVES:Increased renal sinus fat (RSF) is associated with hypertension and chronic kidney disease, but underlying mechanisms are incompletely understood. We evaluated relations between RSF and gold-standard measures of renal hemodynamics in type 2 diabetes (T2D) patients. METHODS:Fifty-one T2D patients [age 63?±?7 years; BMI 31 (28-34) kg/m2; GFR 83?±?16 mL/min/1.73 m2] underwent MRI-scanning to quantify RSF volume, and subcutaneous and visceral adipose tissue compartments (SAT and VAT, respectively). GFR and effective renal plasma flow (ERPF) were determined by inulin and PAH clearances, respectively. Effective renal vascular resistance (ERVR) was calculated. RESULTS:RSF correlated negatively with GFR (r?=?- 0.38; p?=?0.006) and ERPF (r?=?- 0.38; p?=?0.006) and positively with mean arterial pressure (MAP) (r?=?0.29; p?=?0.039) and ERVR (r?=?0.45, p?=?0.001), which persisted after adjustment for VAT, MAP, sex, and BMI. After correction for age, ERVR remained significantly related to RSF. CONCLUSIONS:In T2D patients, higher RSF volume was negatively associated to GFR. In addition, RSF volume was positively associated with increased renal vascular resistance, which may mediate hypertension and CKD development. Further research is needed to investigate how RSF may alter the (afferent) vascular resistance of the renal vasculature.
| S-EPMC7021744 | biostudies-literature
Project description:Neonatal beta-cells undergo a maturation process to acquire glucose responsiveness. We hypothesize that in later life, a partial reversal of this maturation might promote beta-cell dysfunction. We previously ascertained that fetuin-A, a fetal glycoprotein downregulated at birth but increasingly secreted when fatty liver develops, inhibits insulin secretion. Here, we evaluate fetuin-A’s impact on beta-cell maturation. In vitro maturation of neonatal porcine islet cell clusters (NICCs) promoted expression of beta-cell markers and TGFBR/SMAD signaling. Fetuin-A reduced both functional and proliferative gene expression and SMAD phosphorylation. Consequently, fetuin-A impaired glucose- and forskolin-dependent secretion, and reduced adaptive beta-cell proliferation. In adult human islets, fetuin-A abolished glucose responsiveness, diminished SMAD phosphorylation and downregulated functional and proliferative genes. Our findings suggest that perinatal decline of fetuin-A relieves TGFBR signaling in neonatal beta-cells, thereby facilitating the onset of postnatal maturation. However, this program remains revocable during adulthood, since fatty liver-derived fetuin-A reverses beta-cells’ maturity, conferring them a neonatal-like phenotype and contributing to their failure.
2020-12-07 | GSE144950 | GEO
Project description:Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.
| S-EPMC9329397 | biostudies-literature
Project description:BackgroundIn the current Tumour-Node-Metastasis (TNM) classification system for renal cell carcinoma (RCC), both renal sinus fat invasion (SFI) and perinephric fat invasion (PFI) are defined as T3a, suggesting that the prognosis should be similar for the two pathologic findings. Several studies, however, have reported a worse prognosis for SFI in patients with a T3a tumor. In order to compare the prognosis of these two pathologic findings (SFI versus. PFI) in a more comprehensive way, this meta-analysis was performed.MethodsTo identify relevant studies, Medline, Embase, Cochrane Library, and Scopus database were searched from the inception until October 2014. A meta-analysis was performed using Review Manager 5.2 and STATA 11. Pooled Odds ratio (OR) and/or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard association.ResultsA total of 6 studies including 1031 patients qualified for analysis. T3a RCC patients with SFI were significantly associated with poor cancer specific survival(CSS) (HR: 1.47, 95% CI: 1.19-1.83; P<0.001) compared to those with PFI. In T3aNx/N0M0 subgroup, SFI patients also showed a worse prognosis than those with PFI (CSS, HR: 1.94, 95% CI: 1.21-3.12; P = 0.006). T3a RCC patients with SFI had higher Furhman grade, greater possibility of lymph node metastasis, sarcomatoid differentiation and tumour necrosis. Main limitation is the relatively small number of included studies.ConclusionThe present meta-analysis suggested that SFI is associated with worse CSS in patients with pT3a RCC. However, due to the small number of included studies, future studies with a large sample size are required to further verify our findings.
| S-EPMC4758757 | biostudies-literature
Project description:ObjectivesRenal ischemia-reperfusion injury causes acute renal failure, and the hallmarks of renal ischemia-reperfusion injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiologic processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal ischemia-reperfusion injury.DesignProspective, controlled, and randomized animal study.Setting: A research institute laboratory.SubjectsMale C57BL/6J mice (20-25 g).Interventions: Renal ischemia-reperfusion injury with bilateral renal pedicle clamping for 45 mins, followed by reperfusion. A recombinant murine MFG-E8 (0.4 μg/20 g) was given intraperitoneally at the beginning of reperfusion.Measurements and main resultsMFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hrs after reperfusion. A 60-hr survival study was conducted in MFG-E8 and recombinant murine MFG-E8-treated wild-type mice. After renal ischemia-reperfusion injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with recombinant murine MFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8 mice showed a significant deterioration and, in contrast, recombinant murine MFG-E8-treated wild-type mice showed a significant improvement of survival compared with vehicle-treated wild-type mice.ConclusionsMFG-E8 can be developed as novel treatment for renal ischemia-reperfusion injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.
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Project description:Thermogenesis is an important contributor to whole body energy expenditure and metabolic homeostasis. Although circulating factors that promote energy expenditure are known, endocrine molecules that suppress energy expenditure have remained largely elusive. Here we show that Tsukushi (TSK) is a liver-enriched secreted factor that is highly inducible in response to increased energy expenditure. Hepatic Tsk expression and plasma TSK levels are elevated in obesity. TSK deficiency increases sympathetic innervation and norepinephrine release in adipose tissue, leading to enhanced adrenergic signaling and thermogenesis, attenuation of brown fat whitening and protection from diet-induced obesity in mice. Our work reveals TSK as part of a negative feedback mechanism that gates thermogenic energy expenditure and highlights TSK as a potential target for therapeutic intervention in metabolic disease.
| S-EPMC6750233 | biostudies-literature
Project description:Renal sinus fat is partially characteristic of peri-vascular adipose tissue, however, RSF volume (RSFV) is associated with visceral adipose tissue (VATV). Therefore, the ratio of RSFV to VATV (RSFV/VATV ratio) can distinguish the importance of RSF as an extension of VAT versus its perivascular effects. We assessed the association of RSFV/VATV ratio with coronary artery calcification score (CACS) in 189 patients with suspected coronary artery disease. RSFV of the right kidney and VATV were quantified by using image data of unenhanced abdominal CT. CACS were measured on unenhanced ECG-gated CT images. This article contains data on explanatory scheme of how to measure RSFV on unenhanced abdominal CT, CT indication and exclusion criteria of study population, sex-adjusted association between RSFV with risk factors of coronary vascular diseases and metabolic indices, multivariate linear regression analysis with CACS as the dependent variable in the total study population. The data are supplemental to our original research article describing detailed association between RSFV/VATV ratio and CACS including sub-groups analyses classified by the age of 70 "Renal sinus fat volume on computed tomography in middle-aged patients at risk for cardiovascular disease and its association with coronary artery calcification" Murakami et al. [1].
| S-EPMC4872677 | biostudies-literature
Project description:Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized.The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT) were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1) age, (2) age and body mass index (BMI), and (3) age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS) for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs). Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n=16), BMI (n=32), and waist-to-hip ratio (WHR, n=14), and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat.The heritability of renal sinus fat was 39% (p<0.0001); results were not materially different after adjustment for BMI (39%) or VAT (40%). No SNPs reached genome-wide significance in our GWAS. In our candidate gene analysis, we observed nominal, direction consistent associations with renal sinus fat for one SNP associated with renal function (p=0.01), two associated with BMI (p<0.03), and two associated with WHR (p<0.03); however, none remained significant after accounting for multiple testing. Finally, we observed that in aggregate, the 32 SNPs associated with BMI were nominally associated with renal sinus fat (multi-SNP genetic risk score p=0.03).Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity.
| S-EPMC3243045 | biostudies-literature
Project description:PURPOSE:We hypothesize that MRI-based renal compartment volumes, particularly renal sinus fat as locally and potentially independently acting perivascular fat tissue, increase with glucose intolerance. We therefore analyze the distribution of renal volumes in individuals with normal glucose levels and prediabetic and diabetic individuals and investigate potential associations with other typical cardiometabolic biomarkers. MATERIAL AND METHODS:The sample comprised N = 366 participants who were either normoglycemic (N = 230), had prediabetes (N = 87) or diabetes (N = 49), as determined by Oral Glucose Tolerance Test. Other covariates were obtained by standardized measurements and interviews. Whole-body MR measurements were performed on a 3 Tesla scanner. For assessment of the kidneys, a coronal T1w dual-echo Dixon and a coronal T2w single shot fast spin echo sequence were employed. Stepwise semi-automated segmentation of the kidneys on the Dixon-sequences was based on thresholding and geometric assumptions generating volumes for the kidneys and sinus fat. Inter- and intra-reader variability were determined on a subset of 40 subjects. Associations between glycemic status and renal volumes were evaluated by linear regression models, adjusted for other potential confounding variables. Furthermore, the association of renal volumes with visceral adipose tissue was assessed by linear regression models and Pearson's correlation coefficient. RESULTS:Renal volume, renal sinus volume and renal sinus fat increased gradually from normoglycemic controls to individuals with prediabetes to individuals with diabetes (renal volume: 280.3±64.7 ml vs 303.7±67.4 ml vs 320.6±77.7ml, respectively, p < 0.001). After adjustment for age and sex, prediabetes and diabetes were significantly associated to increased renal volume, sinus volume (e.g. βPrediabetes = 10.1, 95% CI: [6.5, 13.7]; p<0.01, βDiabetes = 11.86, 95% CI: [7.2, 16.5]; p<0.01) and sinus fat (e.g. βPrediabetes = 7.13, 95% CI: [4.5, 9.8]; p<0.001, βDiabetes = 7.34, 95% CI: [4.0, 10.7]; p<0.001). Associations attenuated after adjustment for additional confounders were only significant for prediabetes and sinus volume (ß = 4.0 95% CI [0.4, 7.6]; p<0.05). Hypertension was significantly associated with increased sinus volume (β = 3.7, 95% CI: [0.4, 7.0; p<0.05]) and absolute sinus fat volume (β = 3.0, 95% CI: [0.7, 5.3]; p<0.05). GFR and all renal volumes were significantly associated as well as urine creatinine levels and renal sinus volume (β = 1.6, 95% CI: [0.1, 2.9]; p<0.05). CONCLUSION:Renal volume and particularly renal sinus fat volume already increases significantly in prediabetic subjects and is significantly associated with VAT. This shows, that renal sinus fat is a perivascular adipose tissue, which early undergoes changes in the development of metabolic disease. Our findings underpin that renal sinus fat is a link between metabolic disease and associated chronic kidney disease, making it a potential imaging biomarker when assessing perivascular adipose tissue.
| S-EPMC7029849 | biostudies-literature