ABSTRACT
Obesity related glomerulopathy (ORG), as a disease with an increasing incidence of metabolic kidney injury, has become a new hot spot in today's society. A variety of factors are involved in the occurrence and development of ORG. Among them, the ectopic deposition of kidney lipids is not only a significant feature of ORG, but also a key link to promote the progress of ORG. This article reviews the related mechanisms of lipid deposition in ORG and the treatment of ORG with lipid deposition as the target.
ABSTRACT
Objective:To evaluate perirenal adipose tissue inflammation in obesity-related glomerulopathy induced by a high-fat diet in C57BL/6J mice and further explore its probable mechanism.Methods:Twelve 8-10-week-old male C57BL/6J mice were divided into normal diet group (ND, n=6) and high-fat diet group (HFD, n=6) using simple random sampling method. After 14 weeks, the blood and kidney tissue were sampled, and the pathological change in the kidney and perirenal adipose tissue was observed by hematoxylin-eosin, periodic acid-Schiff, and Masson staining. The mRNA expression of tumor necrosis factor-α (TNF-α), M1-type macrophage marker CD11c, interleukin (IL)-1β, monocyte chemotactic protein-1 (MCP-1), IL-10, transforming growth factor-β1, M2-type macrophage marker CD206 and fibronectin 1 in perirenal fat was detected by real-time fluorescence quantitative PCR. The expression of macrophages marker F4/80, CD68 and leukocyte common antigen (LCA) in the kidney and perirenal adipose tissue was detected by immunohistochemistry. Results:After 14 weeks of feeding, compared with mice in the ND group, the weight of mice in the HFD group was significantly higher [(35.83±1.19) g vs (24.06±0.37) g, P<0.05]. In the HFD group, perirenal adipocyte hyperplasia, accompanied by glomerular hyperplasia, mesangial matrix hyperplasia and renal interstitial fibrosis, and other pathological changes was observed (all P<0.05). The level of blood glucose, blood lipid, serum creatinine and blood urea nitrogen was also significantly higher (all P<0.05). The mRNA expression of TNF-α, CD11c, IL-1β and MCP-1 related to M1 macrophages in the perirenal adipose tissue was higher (all P<0.05), and immunohistochemistry showed that the expression of F4/80, CD68 and LCA in the perirenal adipose tissue was higher in HFD group (all P<0.05). The above results showed that the number of macrophages and inflammatory cells in the perirenal adipose tissue was significantly greater in the HFD group than those in the ND group. Pearson linear correlation analysis showed that the average perirenal fat area was positively correlated with macrophages number in perirenal adipose tissue, several morphological indexes such as glomerular cross-sectional area and renal function injury indexes such as blood urea nitrogen (all P<0.05). Conclusion:The C57BL/6J mice model of obesity-related glomerulopathy induced by a high-fat diet is successfully established, and the perirenal adipose tissue shows an obvious inflammatory response, with the macrophages significantly polarized mainly in the pro-inflammatory direction towards the M1-type macrophages.
ABSTRACT
Background@#The nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome composed of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 is engaged in the inflammatory response of many kidney diseases and can be activated by purinergic 2X7 receptor (P2X7R). This study was conducted to explore whether P2X7R plays a pathogenic role in the podocyte damage of obesity-related glomerulopathy (ORG) and whether this role is mediated by the activation of NLRP3 inflammasome.@*Methods@#A mouse model of ORG was established by high-fat diet feeding. The conditionally immortalized mouse podocytes were cultured with leptin or with leptin and P2X7R antagonist (KN-62 or A438079). The mRNA and protein expression of the P2X7R and NLRP3 inflammasome components including NLRP3, ASC, and caspase-1, as well as the podocyte-associated molecules including nephrin, podocin, and desmin in mouse renal cortex or cultured mouse podocytes were tested by real-time-polymerase chain reaction and Western blot analysis, respectively.@*Results@#The significantly upregulated expression of P2X7R and NLRP3 inflammasome components and the NLRP3 inflammasome activation were observed in the renal cortex (in fact their location in podocytes was proved by confocal microscopy) of ORG mice in vivo, which were accompanied with the morphological changes of podocyte damage and the expression changes of podocyte-associated molecules. Similar changes in the expression of P2X7R and NLRP3 inflammasome components as well as in the expression of podocyte-associated molecules were also observed in the cultured podocyte studies treated by leptin in vitro, and all of the above changes were significantly attenuated by the P2X7R antagonist KN-62 or A438079.@*Conclusions@#P2X7R could trigger the activation of NLRP3 inflammasome, and the activated P2X7R/NLRP3 inflammasome in podocytes might be involved in the podocyte damage of ORG.
Subject(s)
Animals , Male , Mice , Blotting, Western , Body Weight , Physiology , Inflammasomes , Metabolism , Kidney Glomerulus , Metabolism , Pathology , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Genetics , Metabolism , Obesity , Podocytes , Metabolism , Pathology , Receptors, Purinergic P2X7 , Genetics , MetabolismABSTRACT
Objective To detect the level of serum α-klotho in different obese people and to investigate the correlation between serum α-klotho and obesity-related glomerulopathy (ORG).Methods A total of 48 cases of ORG diagnosed by renal biopsy were enrolled in the study.Fortyeight gender-,age-and BMI-matched obese participants,and 48 obese chronic kidney disease (CKD) patients without ORG were included as controls.The clinical manifestations,laboratory examinations of all three groups were collected,and the level of serum α-klotho protein was measured by ELISA.Results The patients with ORG were characterized by decreased serum α-klotho concentration compared with obese patients group and obese CKD patients group [572.66(439.92,690.58) pg/ml vs 635.85(559.52,769.20) pg/ml and 690.30(516.15,828.20) pg/ml,P＜ 0.01].Multinomial multiple logistic regression analysis revealed that serum α-klotho (per 100 pg/ml increased) was independently associated with the prevalence of ORG,and the risk of ORG decreased by 35％ in the obese participants (OR=0.652,95％ CI:0.487-0.872) and 38％ in CKD patients (OR=0.617,95％ CI:0.453-0.832) respectively.Conclusions The level of serum α-klotho is significantly decreased in ORG and associated with the prevalence of ORG independently.Serum α-klotho may be a protective factor for ORG.
ABSTRACT
Objective To investigate the relationship of α-klotho protein and obesity related glomerulonephritis.Methods The chronic kidney disease (CKD) patients with or without ORG were diagnosed by renal biopsy.The normal and abdominal obesity control people were enrolled from the physical examination center.Propensity scoring analysis was done to balance the four groups of people in important clinical characteristics.The α-klotho levels in blood and urine were detected by ELISA.ORG mouse model was established and the mRNA and protein expression of klotho protein were detected by real-time quantitative PCR and Western blotting.Results (1) The plasma α-klotho levels decreased in ORG patients,CKD patients and abdominal obesity control people compared with normal control people [(251.7 ± 124.1) ng/L,(336.3 ± 126.1) ng/L,(377.1 ± 120.4) ng/L vs (472.3 ± 204.2)ng/L,all P ＜ 0.05].The ORG patients had the lowest plasma α-klotho levels (P ＜ 0.05).(2) ORG patients also had the lowest urine α-klotho levels compared with CKD patients,abdominal obesity and normal control people [(24.7±11.4) mg/mol vs (82.5±33.8) mg/mol,(74.5±32.5) mg/mol,(100.8±51.1)mg/mol,all P ＜ 0.05].There was no difference in urine α-klotho levels of CKD patients,abdominal obesity and normal control people.(3) Compared with the normal control mouse,ORG model mouse showed decreased mRNA and protein expression of α-klotho protein in renal tissue.Conclusion The lower plasma and urine α-klotho levels in ORG patients may be due to the reduced expression of α -klotho protein in kidney.
ABSTRACT
Objective To explore the relationship between transforming growth factor-β1 (TGF-β1) and obesity-related glomerulopathy (ORG),and to analyze the possible mechanism for ORG and the new approach to its treatment.Methods Based on their body weight,30 SD rats were randomly divided into 2 groups : the normal control group (15 rats) fed with common food and the ORG model group (15 rats) fed with fat-enriched diets.The rats were sacrificed at the end of the 8th week,and their kidneys were taken out.Immunohistochemistry was used to detect TGF-β1 protein expression.Real time (RT)-polymerase chain reaction (PCR) was used to extract and detect the expression of TGF-β1 mRNA,and Western blot was applied to examine the expression of TGF-β1 protein.The findings were analyzed by using SPSS 13.0 software.Results Compared with the control group, qualitative TGF-β1 expression in ORG model group were significantly increased detected by immunohistochemistry mainly in renal tubules and interstitium.The average absorbance value of the control group and the model ORG group was 0.040-0.013,0.171 ± 0.084, respectively.The difference was statistically significant(P ＜ 0.05).The expression of TGF-β1 mRNA detected by RT-PCR was also increased compared with that of the control group(4.4 vs 0.6).The difference was statistically significant(P ＜ 0.05).The protein expression of TGF-β 1 examined by Western blot showed that it was more than that in the control group(4.3 vs 0.4).The difference between the control group and ORG model group was statistically significant(P =0.002).Conclusions The expression of TGF-β 1 in kidneys of ORG model rats increased, which not only indicates it can participate in ORG's occurrence and development, but also provide the basis to find out the mechanism and the approach to treatment.
ABSTRACT
Objective To investigate the effects of peroxisome proliferator-activated receptor γ (PPARγ) agonist on serum adiponectin (ADP),urine microalbumin (mALB) and kidney pathology of obese mice,and discuss the significance of PPARγagonists preventing obesity-related glomerulopathy (ORG).Methods Sixteen male ob/ob mice and 8 male C57BL/6 mice which were 8 weeks old were selected in this study.Ob/ob mice were dividing into 2 groups according to body mass:obesity group (M group) and pioglitazone intervention group (T group) which were fed with high lipid chow.C57BL/6 mice were control group (C group) which were fed with ordinary chow for 12 weeks.Body mass,blood glucose,serum ADP,urine mALB were assayed in each group and compared.The morphological changes of kidney were observe by HE staining,glomerular diameters were measured and compared.Zonula occludens-1 (ZO-1) and Wilms tumor 1 (WT1) were positioned by immunohistochemistry,the level of ZO-1 expression in podocyte and podocyte number which was signed with WT1 in each group were evaluated and compared.And then the correlations between serum ADP,urine mALB,body mass,blood glucose,kidney mass,glomerular diameter,the level of ZO-1 expression,podocyte number were analyzed.Results The serum ADP of obese mice decreased (P ＜ 0.05),and the urine mALB increased (P ＜ 0.05),when compared with that of control group,and there was a negative correlation between ADP and mALB (r =-0.538,P ＜ 0.01).Renal pathology showed glomerular hypertrophy,in part associated with focal segmental glomerulosclerosis (FSGS),the expression of ZO-1 in podocyte and podocyte number were lower than that of control group (P ＜ 0.05).After the intervention with pioglitazone,the urine mALB of obese mice reduced (P ＜ 0.01),and the serum ADP level of them was higher than that of obese mice without intervention (P ＜ 0.01).There was no glomerular hypertrophy and glomerulosclerosis in kidney of obese mice,the expression of ZO-1 in podocyte and podocyte number were higher tban that of obese mice without intervention (P ＜ 0.05).Conclusions The kidneys of obese mice have clinical and pathological changes indicating that obesity can lead to kidney damage.Pioglitazone can make the low serum ADP level of obese mice ameliorated,and make the urine mALB of them reduced.Renal pathological change significantly is alleviated,the expression of ZO-1 in podocyte and podocyte number are increased,indicating pioglitazone can improve renal injury related to obesity.
ABSTRACT
Objective To examine whether aldosterone contribute to obesity related glomerular disease. Methods C57BL/6J mice were randomly divided into three groups: a control group (low?fat?diet, n=10), a model group (high?fat?diet, n=10) and a intervention group (high?fat?diet, n=12). After 8 weeks intervention group were treated with a mineralocorticoid receptor antagonist, spirolactone (SPL).The physicochemical indexes and the renal pathology of the three groups were all detected. The mRNA and protein expressions of podocyte marker protein were determined by real?time PCR and Western blotting, respectively. Results Compared with the control group, body weight, kidney weight, Lee ’s index, fat index, blood cholesterol, blood triglyceride, creatinine clearance rate, urinary protein excretion, glomerular average diameter, glomerular foot process average width were significantly up ? regulated (P<0.05); The mRNA and protein expression of nephrin, podocin, podoplanin and podocalyxin were significantly down?regulated in model group (P<0.05). Meanwhile, these changes were attenuated by SPL. Conclusion Aldosterone can participate in the process of obesity? related renal injury, and these can be attenuated by mineralocorticoid receptor antagonist, spirolactone. This gives us preliminary clues to treat ORG.