Knockout of Toll-Like Receptors 2 and 4 Prevents Renal Ischemia-Reperfusion-Induced Cardiac Hypertrophy in Mice

Abstract

We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.

Lentivirus-Mediated Silencing of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 Inhibits Release of Inflammatory Cytokines and Apoptosis in Renal Tubular Epithelial Cells Via Inhibition of the TLR4/NF-kB Pathway in Renal Ischemia-Reperfusion Injury

“…Interestingly, a previous study revealed that SHP-2 suppressed the expression of TLR3-activated pro-inflammatory cytokine IL-6 and TNF-α, and the silencing of SHP-2 increased the expression of TANK binding kinaseactivated IFN-b and TNF-α [30]. The absence or inhibition of TLRs suppresses cardiac hypertrophy induced by I/R, whereas TLR2 and TLR4 have been shown to mediate systemic inflammatory responses and NF-κB activation [31]. Moreover, inflammation is a key factor in the occurrence and development of ischemic damage, which is secondary to an intense inflammatory response [32].…”

Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling

“…By combining analysis of immunoblot, ELISA and IHC of the same samples, we obtained convincing evidence that I/R‐associated cytoplasmic translocation and extracellular release of HMGB1 can be completely inhibited by either pre‐I/R or delayed FGF2 treatment. As circulating HMGB1 is known to activate proinflammatory signalling pathways through its interaction with pattern recognition receptors such as TLR2 and TLR4; both of which are crucial pro‐inflammatory factors in exacerbating I/RI as demonstrated using their respective knockout mouse models . We therefore further measured the mRNA expression of TLR2 and TLR4 in the kidneys, and confirmed that I/RI significantly induced TLR2 expression, which is completely obliterated upon FGF2 treatment.…”

Anti-inflammatory and anti-apoptotic effects of the combination of Ligusticum chuanxiong and Radix Paeoniae against focal cerebral ischaemia via TLR4/MyD88/MAPK/NF-κB signalling pathway in MCAO rats

“…[31,32] NF-jB and MAPK pathways are proved to be important in the pathogenesis of cerebral ischaemia. [33] TLR5 can constitute as dimerization to activate NF-jB. Several evidences confirmed that the inhibition of TLR4 could protect against ischaemic brain damage and injury in rats.…”

“…The recruitment of the myeloid differentiation primary response protein 88 (MyD88) subsequently facilitates the activation of downstream signalling pathways like the NF‐κB and MAPK pathways by activating TLR4/CD14 . NF‐κB and MAPK pathways are proved to be important in the pathogenesis of cerebral ischaemia . TLR5 can constitute as dimerization to activate NF‐κB.…”