Acute liver injury (ALI) is highly lethal acute liver failure caused by different etiologies. Transforming growth factor β (TGF-β) is a multifunctional cytokine and a well-recognized inducer of apoptotic and necrotic cell death in hepatocytes. Latent TGF-β is activated partly through proteolytic cleavage by a serine protease plasma kallikrein (PLK) between the R58 and L59 residues of its propeptide region. Recently, we developed a specific monoclonal antibody to detect the N-terminal side LAP degradation products ending at residue R58 (R58 LAP-DPs) that reflect PLK-dependent TGF-β activation. This study aimed to explore the potential roles of PLK-dependent TGF-β activation in the pathogenesis of ALI. We established a mouse ALI model via the injection of anti-Fas antibodies (Jo2) and observed increases in the TGF-β1 mRNA level, Smad3 phosphorylation, TUNEL-positive apoptotic hepatocytes and R58-positive cells in the liver tissues of Jo2-treated mice. The R58 LAP-DPs were observed in/around F4/80-positive macrophages, while macrophage depletion with clodronate liposomes partly alleviated the Jo2-induced liver injury. Blocking PLK-dependent TGF-β activation using either the serine proteinase inhibitor FOY305 or the selective PLK inhibitor PKSI-527 or blocking the TGF-β receptor-mediated signaling pathway using SB431542 significantly prevented Jo2-induced hepatic apoptosis and mortality. Furthermore, similar phenomena were observed in the mouse model of ALI with the administration of acetaminophen (APAP). In summary, R58 LAP-DPs reflecting PLK-dependent TGF-β activation may serve as a biomarker for ALI, and targeting PLK-dependent TGF-β activation has potential as a therapeutic strategy for ALI.

04 Mar 2018·Immunopharmacology and Immunotoxicology

Inhibition of plasma kallikrein–kinin system to alleviate renal injury and arthritis symptoms in rats with adjuvant-induced arthritis

Article

Author: Wei, Wei ; Zhu, Jie ; Chen, Jingyu ; Wang, Hui

BACKGROUNDRheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Impairment of kidney functions in RA was observed. However, the mechanism of kidney injury of RA has not been clear. Plasma kallikrein-kinin system (KKS) was involved in inflammatory processes in kidney disease.AIMThis study aimed to explore the role of plasma KKS in immune reactions and kidney injury of RA.RESULTSThe paw of AA rats appeared to be swelling and redness, the arthritis index was significantly increased on the 18, 21 and 24 d after injection and secondary inflammation in multi-sites was observed. Kidney dysfunction accompanied with inflammatory cell infiltration, tubular epithelial cell mitochondrial swelling and vacuolar degeneration, renal glomerular foot process fusions and glomerular basement membrane thickening were observed in AA rats. The expressions of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) in kidney of AA rats were increased. In addition, expressions of BK, PK, B1R and B2R in the renal tissue of AA rats were up-regulated. Pro-inflammatory cytokines IL-2, IFN-γ and TNF-α were increased and anti-inflammatory cytokines IL-4 and IL-10 were low in kidney. Plasma kallikrein (PK) inhibitor PKSI-527 attenuated arthritis signs and renal damage, and inhibited BK, PK, B1R and B2R expressions. The protein expressions of P38, p-P38 and p-JNK and IFN-γ and TNF-α were inhibited by PKSI-527.CONCLUSIONSThese findings demonstrate that plasma KKS activation contributed to the renal injury of AA rats through MAPK signaling pathway. Plasma KKS might be a potential target for RA therapy.

20 Mar 2016·Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases

[Role of kallikrein kinin system activation in kidney injury induced by trichloroethylene sensitized mice].

Article

Author: Yang, P ; Zhu, Q X ; Liu, M ; Zhang, J X ; Zhang, C ; Zang, D D ; Huang, J

OBJECTIVEThrough testing the expression of complement C3 fragment C3b and iC3b, C5b-9 as well as indexes of KKS before and after using kallikrein-kinin system inhibitor PKSI-527, observing the relevant between KKS and complement system, we preliminary study on the mechanism how KKS works on the renal injury of sensitized mice model induced by trichloroethylene.METHODSFemale BALB/c mice (6~8 weeks) were randomly divided into blank control group (5), TCE treated group (15), PKSI-527+TCE treated group (15). Mice were sensitized with TCE in the 1,3,7,10 days, the first and the last challenge were on day 17 and 19. 24h before every challenge, mice in PKSI-527+TCE group were treated with intraperitoneal injection of KKS inhibitor PKSI-527 inhibitor (50mg/kg). Mice were killed 72h after the last challenge. The function of kidney in mice were detected and kidney B1R, B2R expression were detected using real-time quantitative PCR, mice kidney complement C3 fragments C3b, iC3b and C5b-9 deposition were also detected by chemoimmunology.RESULTSCompared with blank control group, all indexes expressions in the solvent control group have no significant change. Compared with the solvent control group, BUN、Cr level and B1R、B2R level have an significant increase (P< 0.05) in TCE sensitized group and PKSI-527+TCE sensitized group; There is a sharp decrease in PKSI-527+TCE sensitized group compared to TCE sensitized group(P< 0.05).CONCLUSIONThe renal damage in the TCE sensitization mouse model may aggravated by upregulate complement system followed by the activation of kallikrein-kinin system.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Preclinical	JP	Resonac Holdings Corp.	-

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