FP028
MICROECOLOGICAL DYSBIOSIS OF GUT MICROBIOTA CONTRIBUTES TO DIABETIC NEPHROPATHY VIA ACTIVATING INTRARENAL RENIN ANGIOTENSIN SYSTEM

INTRODUCTION AND AIMS: It is well-known that activated renal rennin-angiotensin (RAS) plays a key role in the developmentof early diabetic nephropathy (DN). However, the initiating factors and potential mechanisms led to RAS activationhave not been fully elucidated. This study aimed to investigate the underlying mechanisms of how abnormal intestinalmicroenvironment activates RAS to contribute to early renal injuries of DN.

METHODS: Streptozotocin-induced diabetic rat model was randomly divided into three groups: Control group, diabetic group (DM), and diabetic+antibiotics (DM+AB) group. The rats of DM+AB group were fed for 8 weeks with regular chow and antibiotic mixed liquor (ampicillin 1g/L + vancomycin 0.5g/L + neomycin 1g/L + amphotericin B 0.1g/L). Gene sequencing of intestinal microflora was carried out using 16S-rDNA pyrosequencing technique. The morphological changes to the renal pathology and ultra-microstructures were checked by pathological staining and electron microscopy. The plasma RAS components were determined by radioimmunoassay. The protein expressions of RAS components in the kidneys were determined by immunohistochemical staining and Western blot.

RESULTS: Compared with control group, DM group displayed an abnormal state of gut microbiota, with a significant increase of the production of serum acetate, one of their major metabolites belonging to short chain fatty acids (SCFAs). Glomerular endothelial cells and podocytes were damaged obviously and the basement membrane was thickened in DM group, but administration of antibiotics ameliorated renal injuries caused by DM. Furthermore, the levels of plasma renin activity (PRA), angiotensin II (Ang II) were significantly increased in DM rats, indicative of activated RAS, the degree of which has been reduced by antibiotic treatment. As the important effector of RAS, the corresponding protein expression of angiotensin converting enzyme (ACE) and its receptor AT1R has shown opposite trends compared to DM group: DM+AB group has shown increased expression of ACE and less AT1R, suggesting that treatment of antibiotics possibly inhibited the transition of ACE to Ang II in order to weaken the effects of activated RAS on the progression of DN. These results suggested that disordered intestinal flora and consequent RAS activation are closely related to incipient renal injuries of DN, the potential mechanism of which is possibly concerned with SCFAs.

CONCLUSIONS: Our findings suggested that the dysbiosis of intestinal microflora might be a potential mechanism for the progression of early DN, which leads to kidney injuries via the RAS activation.