Abstract
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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant 81970629), the Jiangsu Province Social Development Project (BE2018744), the Project for Jiangsu Provincial Medical Talent (ZDRCA2016077), the Jiangsu Province Six Talent Peaks Project (2015-WSN-002), the Fundamental Research Funds for the Central Universities (KYCX18-0182, KYCX17-0169, KYZZ15-0061), the Jiangsu Province Ordinary University Graduate Research Innovation Project (SJZZ16-004), and the Joint Project of Southeast University and Pharmaceutical University of China (2242019K3DZ03).
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CCL performed the research, analyzed the data, and wrote the paper; KLM designed and reviewed the paper; ZBH, RW, ZHH, JL, PPC, JXZ, XQL, BYY, and SJH assisted in the research; XZR and BCL analyzed and interpreted the data. All authors read and approved the final paper.
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Lu, Cc., Hu, Zb., Wang, R. et al. Gut microbiota dysbiosis-induced activation of the intrarenal renin–angiotensin system is involved in kidney injuries in rat diabetic nephropathy. Acta Pharmacol Sin 41, 1111–1118 (2020). https://doi.org/10.1038/s41401-019-0326-5
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DOI: https://doi.org/10.1038/s41401-019-0326-5
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