Gut microbiota dysbiosis-induced activation of the intrarenal renin–angiotensin system is involved in kidney injuries in rat diabetic nephropathy

Chen-chen Lu1, Ze-bo Hu1, Ru Wang2, Ze-hui Hong3, Jian Lu1, Pei-pei Chen1, Jia-xiu Zhang1, Xue-qi Li1, Ben-yin Yuan1, Si-jia Huang1, Xiong-zhong Ruan4, Bi-cheng Liu1, Kun-ling Ma1
1 Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing 210009, China
2 Institute of Life Science, Southeast University, Nanjing 210009, China
3 Department of Gentics and Developmental Biology, Southeast University School of Medicine, Nanjing 210009, China
4 Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, UK
Correspondence to: Kun-ling Ma:,
DOI: 10.1038/s41401-019-0326-5
Received: 19 July 2019
Accepted: 31 October 2019
Advance online: 17 March 2020


Some studies have shown that gut microbiota along with its metabolites is closely associated with diabetic mellitus (DM). In this study we explored the relationship between gut microbiota and kidney injuries of early diabetic nephropathy (DN) and its underlying mechanisms. Male SD rats were intraperitoneally injected with streptozotocin to induce DM. DM rats were orally administered compound broad-spectrum antibiotics for 8 weeks. After the rats were sacrificed, their blood, urine, feces, and renal tissues were harvested for analyses. We found that compared with the control rats, DM rats had abnormal intestinal microflora, increased plasma acetate levels, increased proteinuria, thickened glomerular basement membrane, and podocyte foot process effacement in the kidneys. Furthermore, the protein levels of angiotensin II, angiotensin-converting enzyme, and angiotensin II type 1 receptor in the kidneys of DM rats were significantly increased. Administration of broad-spectrum antibiotics in DM rats not only completely killed most intestinal microflora, but also significantly lowered the plasma acetate levels, inhibited intrarenal RAS activation, and attenuated kidney damage. Finally, we showed that plasma acetate levels were positively correlated with intrarenal angiotensin II protein expression (r=0.969, P<0.001). In conclusion, excessive acetate produced by disturbed gut microbiota might be involved in the kidney injuries of early DN through activating intrarenal RAS.
Keywords: diabetic nephropathy; gut microbiota; plasma acetate; renin–angiotensin system; broad-spectrum antibiotics

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