Plasma Kallikrein-Kinin system mediates immune-mediated renal injury in trichloroethylene-sensitized mice

Abstract

Trichloroethylene (TCE) is a major environmental pollutant. An immunological response is a newlyrecognized mechanism for TCE-induced kidney damage. However, the role of the plasma kallikreinkinin system (KKS) in immune-mediated kidney injury has never been examined. This study aimed to explore the role of the key components of the KKS, i.e. plasma kallikrein (PK), bradykinin (BK) and its receptors B1R and B2R, in TCE-induced kidney injury. A mouse model of skin sensitization was used to explore the mechanism of injury with or without a PK inhibitor PKSI. Kidney function was evaluated by measuring blood urea nitrogen (BUN) and creatinine (Cr) in conjunction with histopathologic characterization. Plasma BK was determined by ELISA; Renal C5b-9 membrane attack complex was evaluated by immunohistochemistry. Expression of BK and PK in the kidney was detected by immunoFuorescence. mRNA and protein levels of B1R and B2R were assessed by real-time qPCR and Western blot. As expected, numerous inflammatory cell inEltration and tubular epithelial cell vacuolar degeneration were observed in TCE-sensitized mice. Moreover, serum BUN and Cr and plasma BK were increased. In addition, deposition of BK, PK and C5b-9 were observed and B1R and B2R mRNA and proteins levels were up-regulated. Pre-treatment with PKSI, a highly selective inhibitor of PK, alleviated TCE-induced renal damage. In addition, PKSI attenuated TCEinduced up-regulation of BK, PK and its receptors and C5b-9. These results provided the first evidence that activation of the KKS contributed to immune-mediated renal injury induced by TCE and also helped to identify the KKS as a potential therapeutic target for mitigating chemical sensitization-induced renal damage.ARTICLE HISTORY

Bradykinin contributes to immune liver injury via B2R receptor-mediated pathways in trichloroethylene sensitized mice: A role in Kupffer cell activation

“…This begs a further question how KCs and their secreted cytokines are regulated. In our previous study, we found KKS activation and plasma BK expression increased significantly in TCE sensitized mice (Wang et al, 2016). Many studies have revealed BK stimulated macrophage activation and induced inflammatory cytokine expression in immune injury in other tissues (Feng et al, 2016;Vorlova et al, 2016;Desposito et al, 2015).…”

“…Liver KCs were isolated by in situ collagenase perfusion and differential centrifugation on Percoll density gradient as described previously (Hansen et al, 2002;Wu et al, 2016). Briefly, a 20-G catheter was put into the portal vein, and the inferior vena cava cut.…”

“…In our previous studies, we have found that kallikrein-kinin system (KKS) plays an important role in organ injury in trichloroethylene-sensitized mice (Wang et al, 2016;. The mechanism however is unclear.…”

NIOSH skin notation (SK) profile: trichloroethylene (TCE) [CAS No. 79-01-6].

“…The sensitization rate in mice exposed to TCE was 40% (48/120). TDI exposed mice had increased serum urea nitrogen (BUN) and creatinine (Cr) (an indication of how well the kidneys are working) and inflammatory cell infiltration and tubular epithelial cell vacuolar degeneration at 48 and 72 hours after the final challenge with TCE [Wang et al 2016].…”

“…Tang et al [2008] concluded that TCE may be capable of inducing dermatitis and liver damage, on the basis of delayed-type hypersensitivity in guinea pigs. Wang et al [2016] evaluated immune-mediated renal injury of TCE on BALB/c mice that received an intradermal injection of 100 µL of 50% TCE on day one, 100 µL of 50% TCE painted on clipped dorsal skin on days four, seven, and ten, and was challenged with 100 µL on clipped dorsal skin on days 17 and 19. The sensitization rate in mice exposed to TCE was 40% (48/120).…”