Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis

Hu, Ze Bo; Lü, Jian; Chen, Pei Pei; Chen, Lu; Zhang, Jia Xiu; Li, Xue Qi; Yuan, Ben Yin; Huang, Si Jia; Ruan, Xiong Z.; Liu, Bi Cheng; Ling, Kun

doi:10.7150/thno.40571

Cited by 69 publications

(59 citation statements)

References 41 publications

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“…The gut microbiota has been proven to be an important endogenous factor modulating BAT activity and the browning of WAT 62 , and gut microbiota changes in obese patients are positively linked to the expression of PRDM16 in S-WAT 62 . The induction of browning through the transplantation of beneficial gut microbiota has been proved to be an effective therapeutic strategy for treating obesity 11 , 63 , 64 in experimental animal studies 65 . At present, the effects of FMT as a therapy for obesity and related metabolic disorders have been assessed in clinical studies 66 .…”

Section: Discussionmentioning

confidence: 99%

Panax notoginseng saponins modulate the gut microbiota to promote thermogenesis and beige adipocyte reconstruction via leptin-mediated AMPKα/STAT3 signaling in diet-induced obesity

et al. 2020

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Background: Activation of the thermogenic program in white and brown adipocytes presents a promising avenue for increasing energy expenditure during the treatment of obesity. The endogenous mechanism for promoting thermogenesis in brown adipocytes or browning in white adipocytes has indicated that the gut microbiota is a crucial regulator of the host energy balance. However, whether the effects of the therapeutic intervention-induced modulation of the gut microbiota on adipocyte browning involved the regulation of leptin remains unclear. Method: The adipose features were analyzed by body composition analysis, infrared camera observations, transmission electron microscopy and H&E staining. The gene and protein expression in adipose tissue were detected by qRT-PCR, immunoblotting, immunohistochemistry and immunofluorescence staining. The gut microbiome signature was identified by 16S rRNA gene amplicon sequencing, and both mice with high-fat diet-induced obesity (DIO) and mice with antibiotics-induced microbiome depletion were subjected to fecal microbiota transplantation. Results: Treatment with Panax notoginseng saponins (PNS) shaped the murine gut microbiome by increasing the abundances of Akkermansia muciniphila and Parabacteroides distasonis , and as a result, DIO mice harbored a distal gut microbiota with a significantly increased capacity to reduce host adiposity. The PNS-induced modulation of the gut microbiota in DIO mice could increase brown adipose tissue (BAT) thermogenesis and beige adipocyte reconstruction by activating the leptin-AMPK/STAT3 signaling pathway, which results in the promotion of energy expenditure. Leptin has an essential influence on the anti-obesity effects of PNS. In cases of leptin deficiency, the PNS-induced modulation of the gut microbiota exerts negative effects on thermogenesis and browning in white adipose tissue (WAT), which indicates that PNS fail to reduce obesity in leptin gene-deficient mice. The PNS-induced modulation of the gut microbiota exerted a minimal effect on DIO mice with antibiotic-induced microbiome depletion, which confirmed the correlation between altered gut microbiota and the remodeling of adipose tissues in DIO mice. The direct influence of leptin on browning via the AMPKα/STAT3 signaling pathway in C3H101/2 cells supported our in vivo results that signalling through the leptin-AMPK/STAT3 pathway induced by the PNS-modulated gut microbiota was involved in beige adipocyte reconstruction. Conclusion : Our results revealed that leptin signaling is critical for alterations in microbiota-fat crosstalk and provide promising avenues for therapeutic intervention in the treatment of obesity.

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Section: Discussionmentioning

confidence: 99%

Panax notoginseng saponins modulate the gut microbiota to promote thermogenesis and beige adipocyte reconstruction via leptin-mediated AMPKα/STAT3 signaling in diet-induced obesity

et al. 2020

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“…Morphological changes of the kidney ultrastructure were evaluated by TEM (Hitachi, Japan). The protocol of sample processing was described in our previous study 19 .…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study demonstrated that the dysbiosis of gut microbiota contributed to the tubulointerstitial injury of DN through the disruption of cholesterol homeostasis 19 . Therefore, using diabetic animal models, GPR43 gene knockout (KO) mice, and cultured podocytes, this study aimed to investigate the possible roles of GPR43 in podocye injury of early DN and to explore its potential mechanisms involved in gut microbiota, insulin resistance, and the modulation of AMPKα activity.…”

Section: Introductionmentioning

confidence: 99%

GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity

Lü¹,

Chen²,

Zhang³

et al. 2021

Theranostics

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Rationale: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. Methods: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. Results: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. Conclusion: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity.

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“…Hu et al have demonstrated that DN rats have a higher serum acetate level, which increases the accumulation of cholesterol in renal epithelial cells by upregulating the expression of G proteincoupled receptor 43 (GPR43), thereby promoting kidney damage in DN rats. After removing intestinal bacteria with antibiotics, the acetate level is reduced, reversing the cholesterol metabolism disorder and renal tubule interstitial damage in DN rats [74]. GPR43 is a receptor for all three SCFAs, acetate, propionate, and butyrate.…”

Section: Dysbiosis In Diabetic Nephropathymentioning

confidence: 99%

Role of the gut microbiota in type 2 diabetes and related diseases

et al. 2021

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Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis

Cited by 69 publications

References 41 publications

Panax notoginseng saponins modulate the gut microbiota to promote thermogenesis and beige adipocyte reconstruction via leptin-mediated AMPKα/STAT3 signaling in diet-induced obesity

Panax notoginseng saponins modulate the gut microbiota to promote thermogenesis and beige adipocyte reconstruction via leptin-mediated AMPKα/STAT3 signaling in diet-induced obesity

GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity

Role of the gut microbiota in type 2 diabetes and related diseases

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