Further, to Fingolimod elucidate the downstream mechanism of renoprotection by BB, we examined the association of TLR4-mediated MAPK activation in MetS-induced kidney dysfunction. Previous findings have established a potential link between ERK1/2 phosphorylation and oxidative stress-induced insulin resistance, which is a characteristic of MetS. Xi L. et al recently showed that selective inhibition of ERK1/2 in rat hepatocytes improved an impaired insulin signaling. In addition, inhibition of p38MAPK signaling pathways have been shown to prevent dietinduced MetS in rats. Although MAPK activation has been shown in LPS-induced kidney dysfunction, a role for the TLR4-MAPK pathway in MetS-induced CKD has never been investigated. Our findings demonstrate phosphorylated-ERK and p38MAPK in OZRCC animals compared to the LZRCC and LZRBB. Interestingly, BB-treated OZR -had suppressed ERK and p38MAPK activity in the kidneys. This inhibition of MAPK activation in OZRBB animals could also be a plausible explanation for the improved glucose sensitivity in these animals. Therefore, these results not only designate a key role of TLR4MAPK signaling in MetS-associated CKD but also indicate a potential mechanism by which BB protects against chronic kidney injury. In addition to attenuated TLR4 and MAPK expression, OZRBB exhibited decreased expression of PICs. We examined the expression of gene and protein expression of IL-1b and IL-18 in the kidney cortex of animals from all experimental groups. The importance of IL-1b and IL-18 expression patterns in this study is particularly important, not only because these are proinflammatory molecules, but also as these are downstream molecules of the TLR4 pathway. We observed that OZRBB animals expressed a significantly lower amount of IL-1b and IL-18 compared to the OZRCC rats. This is consistent with the previous findings from our lab, which reported that in SHR, a renal function decline involves an association of PICs with their transcription factor NFkB. Further, oxidative stress is a key regulator of NFkB activity and it produces a positive feedback mechanism related to inflammation and tissue injury. In this context, we also measured the NFkB activity in all the groups, as NFkB activity is an indicator of TLR4 activation. Our data shows that BB attenuates the NFkB activity in MetS rats, thus confirming the reno-protective effect of BB is, at least in part, mediated by TLR4. NFkB and MAPK pathways regulate the expression of many genes involved in inflammation and tissue injury and their inhibition have been shown to have tissue protective effects. Nrf2 antioxidant pathway is a key mechanism in the attenuation of kidney injury by reno-protective agents. Several mechanisms of Nrf2 activation have been reported, including MAPK signaling pathways. In normal physiological conditions, the MAPK family maintains the much needed balance between NFkB and Nrf2 activation.