Abstract
There is increasing evidence that Chronic Kidney Disease (CKD) can cause intestinal dysfunction, which in turn aggravates the progression of kidney disease. Studies have shown that the immune response of macrophage plays an important role in promoting inflammation in kidney and intestine of CKD. Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) is a widely used traditional medicine for the treatment of CKD in China, however, the underlying mechanism is largely unclear. In this study, we aimed to explore the role of A&P and Bifidobacterium combination treatment in regulation of inflammatory response of macrophage in kidney and intestine of CKD mouse, as well as the potential molecular mechanism. We established a CKD mouse model with 5/6 nephrectomy and a macrophage inflammatory cellular model with LPS and urotoxin in vivo and in vitro. The results showed that A&P combined with Bifidobacterium significantly reduced the expression and secretion of IL-1β, IL-6, TNFα, and MCP-1 in kidney and blood, as well as in inflammatory macrophage. Interestingly, A&P combined with Bifidobacterium strongly improved the intestinal flora and protected the intestinal barrier. Notably, the maintainer of macrophage polarization, Mincle, was activated in kidney and intestine of CKD mouse as well as in urotoxin stimulated macrophage, that was effectively inhibited by the treatment of A&P and Bifidobacterium combination. Overexpression of Mincle by genetic modification can abolish the inhibitory effects of A&P combined with Bifidobacterium on inflammation in urotoxin stimulated RAW264.7 cells. In summary, these findings demonstrated that A&P combined with Bifidobacterium can protect kidney against CKD by down-regulating macrophage inflammatory response in kidney and intestine via suppressing Mincle signaling, which provides a new insight in the treatment of CKD with traditional medicine.
Highlights
Chronic Kidney Disease (CKD), which is defined as the presence of renal structural and/or functional abnormalities for at least 3 months, has been widely regarded as an important public health problem
These results suggested that A&P combined with bifidobacterium treatment can significantly improve the body weight and renal function in CKD mice
The western blot results proved the up-regulation of ZO-1, Occludin1 and claudin-1 protein levels in A&P and Bifidobacterium combination group compared with the CKD model group (Figure 3E). These results suggested that A&P combined with Bifidobacterium had a protective effect on intestinal barrier of CKD mice
Summary
Chronic Kidney Disease (CKD), which is defined as the presence of renal structural and/or functional abnormalities for at least 3 months, has been widely regarded as an important public health problem. In the advanced stage of chronic kidney disease, metabolic waste cannot be excreted by the intestine and kidney, and is accumulated in the body in large amounts, which may further enter the intestinal wall through blood vessels. Increased urotoxin in blood after kidney injury enter the intestine wall, which promotes fundamental changes of the living environment of intestinal epithelium and intestinal flora, leading to an increase of the number of pathogenic bacteria and a reduction of beneficial bacteria, which directly or indirectly promotes the entry of toxins into intestinal epithelial cells, causing severe damage to the structure and function of intestinal barrier. Using modern medical methods to explore the mechanism of the intestinal microecological balance and the interaction between intestinal mucosal barrier function and CKD through animal model in vivo and cellular model in vitro are new directions worth exploring (Crespo-Salgado et al, 2016; Nallu et al, 2017)
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