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

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

doi:10.7150/thno.40571

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Nanotheranostics 2024; 8(3): 380-400. [Abstract] [Full text] [PDF]

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Theranostics 2020; 10(6):2803-2816. doi:10.7150/thno.40571 This issue Cite

Research Paper

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

Ze Bo Hu^1,2, Jian Lu¹, Pei Pei Chen¹, Chen Chen Lu¹, Jia Xiu Zhang¹, Xue Qi Li¹, Ben Yin Yuan¹, Si Jia Huang¹, Xiong Zhong Ruan³, Bi Cheng Liu¹, Kun Ling Ma^1✉

1. Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
2. Department of Pathophysiology, School of Basic Medicine, Wannan Medical College, Wuhu, 241002, China.
3. Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, UK.

Citation:

Hu ZB, Lu J, Chen PP, Lu CC, Zhang JX, Li XQ, Yuan BY, Huang SJ, Ruan XZ, Liu BC, Ma KL. Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis. Theranostics 2020; 10(6):2803-2816. doi:10.7150/thno.40571. https://www.thno.org/v10p2803.htm

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Abstract

Background: Our previous study demonstrated that the disruption of cholesterol homeostasis promotes tubulointerstitial injury in diabetic nephropathy (DN). This study aimed to further investigate the effects of gut microbiota dysbiosis on this process and explored its potential mechanism.

Methods: Diabetic rats treated with broad-spectrum oral antibiotics or faecal microbiota transplantation (FMT) from the healthy donor group and human kidney 2 (HK-2) cells stimulated with sodium acetate were used to observe the effects of gut microbiota on cholesterol homeostasis. The gut microbiota distribution was measured by 16S rDNA sequencing with faeces. Serum acetate level was examined by gas chromatographic analysis. Protein expression of G protein coupled receptor 43 (GPR43) and molecules involved in cholesterol homeostasis were assessed by immunohistochemical staining, immunofluorescence staining, and Western Blotting.

Results: Depletion of gut microbiota significantly attenuated albuminuria and tubulointerstitial injury. Interestingly, serum acetate levels were also markedly decreased in antibiotics-treated diabetic rats and positively correlated with the cholesterol contents in kidneys. An in vitro study demonstrated that acetate significantly increased cholesterol accumulation in HK-2 cells, which was caused by increased expression of proteins mainly modulating cholesterol synthesis and uptake. As expected, FMT effectively decreased serum acetate levels and alleviated tubulointerstitial injury in diabetic rats through overriding the disruption of cholesterol homeostasis. Furthermore, GPR43 siRNA treatment blocked acetate-mediated cholesterol homeostasis dysregulation in HK-2 cells through decreasing the expression of proteins governed cholesterol synthesis and uptake.

Conclusion: Our studies for the first time demonstrated that the acetate produced from gut microbiota mediated the dysregulation of cholesterol homeostasis through the activation of GPR43, thereby contributing to the tubulointerstitial injury of DN, suggesting that gut microbiota reprogramming might be a new strategy for DN prevention and therapy.

Keywords: diabetic nephropathy, gut microbiota, acetate, cholesterol homeostasis, tubulointerstitial injury

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APA

Hu, Z.B., Lu, J., Chen, P.P., Lu, C.C., Zhang, J.X., Li, X.Q., Yuan, B.Y., Huang, S.J., Ruan, X.Z., Liu, B.C., Ma, K.L. (2020). Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis. Theranostics, 10(6), 2803-2816. https://doi.org/10.7150/thno.40571.

ACS

Hu, Z.B.; Lu, J.; Chen, P.P.; Lu, C.C.; Zhang, J.X.; Li, X.Q.; Yuan, B.Y.; Huang, S.J.; Ruan, X.Z.; Liu, B.C.; Ma, K.L. Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis. Theranostics 2020, 10 (6), 2803-2816. DOI: 10.7150/thno.40571.

NLM

CSE

Hu ZB, Lu J, Chen PP, Lu CC, Zhang JX, Li XQ, Yuan BY, Huang SJ, Ruan XZ, Liu BC, Ma KL. 2020. Dysbiosis of intestinal microbiota mediates tubulointerstitial injury in diabetic nephropathy via the disruption of cholesterol homeostasis. Theranostics. 10(6):2803-2816.

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