Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury

Abstract

Toll-like receptors (TLRs) are an evolutionarily conserved family of cell membrane receptors that are part of the innate immunity system playing an important role as a first response to tissue injury. TLR2 and TLR4 are constitutively expressed on renal epithelium, and their expression is enhanced following renal ischemia/reperfusion (I/R) injury. Genetic deletion of either TLR2 or TLR4 protects from renal I/R injury. However, it is not known whether deletion of both combined protects the kidney more than a deletion of either one alone. Therefore, we performed renal I/R injury in mice lacking TLR2, TLR4, and TLR2/4, respectively. Our results demonstrate that there are no significant differences regarding protection from renal I/R injury in TLR2/4((-/-)) compared with either TLR2((-/-)) or TLR4((-/-)) gene-targeted mice as determined by histological evaluation and renal functional parameters. Furthermore, there was no difference in the number of apoptotic tubular cells and in nuclear translocation of nuclear factor kappa-B (NF-kappaB) between the TLR-gene-targeted groups. In parallel, in vitro experiments did not demonstrate an additional effect of the double genetic deletion compared with the single gene deletion with respect to tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 production in hypoxic isolated proximal tubular epithelial cells of the respective animals. In conclusion, a double genetic deletion of TLR2 and TLR4 confers a similar protection following renal I/R injury compared with single deletions of TLR2 and TLR4.

Blocking innate immunity to slow the progression of chronic kidney disease

“…One of the crucial works linking innate immunity and acute kidney injury could show that TLR2-deficient mice are protected from renal ischemia/reperfusion injury (I/R) (Leemans et al 2005). This finding was confirmed for TLR 4 and double-deficient mice for TLR 2/4 in the same model (Rusai et al 2010). Moreover, the blocking of IL-1 RA was able to ameliorate kidney injury in a rat model of I/R (Rusai et al 2008).…”

RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

“…HMGB1 can, however, also induce activation of intracellular signaling pathways via interaction with PRRs other than RAGE including: Toll-like receptor (TLR) 2, TLR-4 and inflammasome NACHT, LRR and PYD domains-containing protein 3 (Nlrp3) [32,33] . We and others have shown that ␣ HMGB1-treated WT mice, TLR2 KO, TLR4 KO and Nlrp3 KO mice display a similar phenotype following renal I/R [16,17,21,30,31,[34][35][36] . Together, these reports implicate that the deleterious effect of HMGB1 in the development of renal I/R injury is not mediated by RAGE signaling, but rather by TLRs and/or Nlrp3.…”

How the Innate Immune System Senses Trouble and Causes Trouble

“…Many PRRs, including TLRs, are expressed in renal epithelial cells (46)(47)(48)(49)(50)(51)(52)(53)(54). The precise distribution of tubular TLRs remains somewhat uncertain.…”