Prevent And Reverse Renal Fibrosis By Modulating The Immune Microenvironment Of Renal Tissue

Chronic kidney diseases(CKD) is one of the most dangous threats to public health. Renal fibrosis is not only the common pathological feature of of all CKDs, but also the major pathogeny for ESRD. Renal fibrosis is defined by the disproportionate accumulation of extracelluar matrix that replaces kidney parenchyma, ultimately leading to renal destruction and dysfunction. Evidences show that immune responses play an important role in the progressive renal fibrosis. It might be an important strategy to retard the progression of renal fibrosis by immune modulation. In our studies, Murine models of renal fibrosis were prepared by unilateral ureteral obstruction (UUO). We explored the potential therapeutic effects and associated anti-fibrotic mechisms of polysaccharides of mushroom CFX and TLR9 agonist(CpG). We found that CFX could up-regulate the expression of TLR2 and TLR4 on cultured renal epithelial cells and show ability to fight against oxidative stress. From one week before UUO, mice received CFX (3g/kg/day) showed less renal fibrotic lesions. The renoprotection of CFX was related to suppress inflammatory responses, attenuate local oxidative stress, inhibit the activity of myofibroblasts, blunt TGF-β/Smad3, TAK and p38MAPK signaling pathways, and down-regulate the apoptotic signal. Furthermore, we found that CFX could reverse the established fibrosis induced by UUO which might be contributed to CFX reshaping immune status. From the 4th day of UUO, animal received CFX, and an up-regulated ratio of Th1/Th2 cells at UUO14d and down-regulated ratio of M2 at UUO21d were observed in spleens. In UUO kidneys, CFX decreased the expression of TGF-βand Smad3, increased expression ratio of IFN-y/TGF-βand inhibited the expression of suppressive molecule Stat3. Additionally, CFX inhibited the chronic inflammatory signal involving MAPKs and NF-κB. In another study, we have examined the role of CpG to renal fibrosis. We found CpG administrated before UUO as a small molecular vaccine, could potentially reduced the numbers of infiltrated macrophage, down-regulated the expression of Th2 cytokine (IL-13) and profibrogenic cytokines (TGF-β1 and PAI-1) in obstructed renals, markly prevented fibrosis induced by UUO. CpG also showed significant efficiency in established renal fibrosis which was related to CpG reversing suppressive immune microenvironment. UUO induced renal fibrosis characterized with the prominent Th2 and M2 response. CpG decreased the production of Th2 cytokines, inhibited the expression of suppressive signal transducer-stat3 and modulated the activity of different MAPK signals. Our studies showed that it was the new strategy to prevent or in some extent reverse renal fibrosis by reshaping immune microenvironment with immune modulators. TLR9 agonists and immune modulator-CFX could be potentially developed new anti-renal fibrosis drugs.