Doctor of Philosophy (PhD)
Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences
Despite advances in its treatment, the incidence of renal diseases has been consistently increasing. Hence, there is a need to understand the underlying molecular mechanisms of the progression of kidney diseases. Recent research implicates inflammation as an important mediator of renal injury. We hypothesized that inhibiting Toll-like receptor 4 (TLR4), an upstream modulator of several inflammatory pathways, would prevent the progression of renal diseases. First, we determined the mechanism by which AngiotensinII (AngII)-induced inflammation is modulated by TLR4 using an in vitro model of rat tubulo-epithelial cells. We blocked TLR4 using gene silencing strategy in NRK52E cells. In TLR4-silenced cells, the expression of TLR4 was decreased, activation of NF-κB was reduced, inflammation and oxidative stress were attenuated, suggesting a role for TLR4 in potentiating AngII-induced renal inflammation. We then focused on an in vivo acute kidney injury (AKI) model to elucidate the effect of TLR4 in AKI. We used lipopolysaccharide (LPS), a specific ligand of TLR4, to induce AKI. We injected one group of rats with VIPER, a TLR4 inhibitory peptide, before LPS administration. We also used blueberry as a non-pharmacological approach to study if blueberry could protect against LPS-induced AKI. Compared to LPS-administered rats, the BB-pretreated animals exhibited improved renal hemodynamics, attenuated expression of TLR4 and inflammation. The results in the BB-pretreated group were consistent with the VIPER-treated rats. This indicates that TLR4 is an important mediator in LPS-induced AKI, and suggest that BB, by inhibiting TLR4, is a viable non-pharmacological option to decrease AKI. We also examined the effect of TLR4 signaling and its downstream mechanism in an animal model of metabolic syndrome-associated chronic kidney disease (CKD) and investigated if a blueberry-enriched diet could attenuate the progression of CKD. We showed that OZR exhibited lower glucose tolerance, exacerbated renal dysfunction and increased oxidative stress. Expression levels of TLR4 and, phosphorylation of ERK and p38MAPK were higher. This was accompanied by increased renal pathology. BB-fed OZR showed significant improvements in all of these parameters. This suggests that the TLR4-MAPK signaling pathway is a key to the renal dysfunction in MetS, and BB protects against this damage by inhibiting TLR4.
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R. Nair, Anand, "Toll-like Receptor 4 (TLR4) in Acute and Chronic Renal Diseases" (2015). LSU Doctoral Dissertations. 3632.