Chaiyabutr Narongsak, Noiprom Jureeporn, Promruangreang Kanyanat, Vasaruchapong Taksa, Laoungbua Panithi, Khow Orawan, Chanhome Lawan, Sitprija Visith
Queen Saovabha Memorial Institute, The Thai Red Cross Society, Pathumwan, Bangkok, Thailand.
Department of Research and Development, Queen Saovabha Memorial Institute, The Thai Red Cross Society, Bangkok, Thailand.
J Venom Anim Toxins Incl Trop Dis. 2024 May 20;30:e20230070. doi: 10.1590/1678-9199-JVATITD-2023-0070. eCollection 2024.
This study examines the direct nephrotoxic effects of venom (RVV) and venom fractions in and isolated perfused kidneys (IPK) to understand the role of inflammation pathways and susceptibility to oxidative stress in venom or fraction-induced acute renal failure.
We administered RVV and its venom fractions (PLA, MP, LAAO, and PDE) to rabbits and in the IPK model. We measured oxidative stress biomarkers (SOD, CAT, GSH, and MDA) in kidney tissue, as well as inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-4, IL-5, and IL-10), MDA and GSH levels in plasma and urine. We also calculated fractional excretion (FE) for pro-/anti-inflammatory cytokines and oxidative stress biomarkers, including the ratios of pro-/anti-inflammatory cytokines in urine after envenomation.
In both kidney models, significant increases in MDA, SOD, CAT, and GSH levels were observed in kidney tissues, along with elevated concentrations of MDA and GSH in plasma and urine after injecting RVV and venom fractions. Moreover, RVV injections led to progressive increases in FE and decreases in FE The concentrations of IL-4, IL-5, IL-10, IFN-γ, and TNF-α in plasma increased , as well as in the urine of the IPK model, but not for IL-1β in both plasma and urine after RVV administrations. Urinary fractional excretion of TNF-α, IL-1β, IFN-γ, IL-4, IL-5, and IL-10 tended to decrease but showed elevated levels in the IPK model. A single RVV injection disrupted the balance of urinary cytokines, significantly reducing either the TNF-α/IL-10 ratio or the IFN-γ/IL-10 ratio.
RVV induces renal tubular toxicity by increasing oxidative stress production and elevating inflammatory cytokines in urine. During the acute phase of acute kidney injury, the balance of urine cytokines shifts toward anti-inflammatory dominance within the first two hours post-RVV and venom fractions.
本研究检测了响尾蛇毒液（RVV）及其毒液组分对家兔和离体灌注肾（IPK）的直接肾毒性作用，以了解炎症途径的作用以及毒液或其组分诱导急性肾衰竭时对氧化应激的易感性。
我们在家兔和IPK模型中给予RVV及其毒液组分（磷脂酶A、金属蛋白酶、L-氨基酸氧化酶和磷酸二酯酶）。我们测量了肾组织中的氧化应激生物标志物（超氧化物歧化酶、过氧化氢酶、谷胱甘肽和丙二醛），以及血浆和尿液中的炎性细胞因子（肿瘤坏死因子-α、白细胞介素-1β、干扰素-γ、白细胞介素-4、白细胞介素-5和白细胞介素-10）、丙二醛和谷胱甘肽水平。我们还计算了促炎/抗炎细胞因子和氧化应激生物标志物的排泄分数（FE），包括中毒后尿液中促炎/抗炎细胞因子的比率。
在两种肾模型中，注射RVV及其毒液组分后，肾组织中丙二醛、超氧化物歧化酶、过氧化氢酶和谷胱甘肽水平显著升高，血浆和尿液中丙二醛和谷胱甘肽浓度也升高。此外，注射RVV导致排泄分数逐渐升高，而排泄分数逐渐降低。血浆中白细胞介素-4、白细胞介素-5、白细胞介素-10、干扰素-γ和肿瘤坏死因子-α的浓度升高，IPK模型的尿液中也是如此，但注射RVV后血浆和尿液中的白细胞介素-1β浓度未升高。肿瘤坏死因子-α、白细胞介素-1β、干扰素-γ、白细胞介素-4、白细胞介素-5和白细胞介素-10的尿排泄分数倾向于降低，但在IPK模型中升高。单次注射RVV会破坏尿液细胞因子的平衡，显著降低肿瘤坏死因子-α/白细胞介素-10比率或干扰素-γ/白细胞介素-10比率。
RVV通过增加氧化应激产生和升高尿液中的炎性细胞因子诱导肾小管毒性。在急性肾损伤的急性期，在注射RVV及其毒液组分后的头两小时内，尿液细胞因子的平衡向抗炎占优势转变。
