RESUMEN
BACKGROUND: Interleukin-17C (IL-17C), a member of the IL-17 cytokine family, plays a pathogenic role in kidney diseases. Our previous studies have shown that pre-administration of IL-17C neutralizing antibody attenuated acute kidney injury (AKI, a common acute inflammation associated renal disease). In this study, we explored whether post-ischemia reperfusion (IR) of IL-17C blockade has therapeutic effects on AKI and whether IL-17C is involved in the pathogenesis of diabetic nephropathy (DN), a major type of chronic inflammation-associated kidney disease. METHODS: 12-week-old male C57BL/6JGpt mice were treated with IL-17C neutralizing antibody or normal IgG control antibody at 3 h after reperfusion. Renal injury, inflammation, and oxidative stress were assessed. Additionally, we examined renal IL-17C expression in patients with DN and db/db mice and evaluated albuminuria, mesangial matrix accumulation and podocyte loss in db/db mice with IL-17C neutralization. Knockdown of NF-κB p65 using siRNA, and blocking Hypoxia-inducible factor-1α (HIF-1α) using YC-1 in mice and HIF-1α Decoy in HK2 cells were investigated to explore the possible signaling pathway involved in IL-17C regulation. FINDINGS: We found that delayed IL-17C neutralization had similar reno-protective effects on renal ischemia-reperfusion injury (IRI). Additionally, renal IL-17C expression was increased in patients with DN and db/db mice, while IL-17C blockade significantly attenuated DN, accompanied with blunted albuminuria, mesangial matrix accumulation, and podocyte loss. Moreover, IL-17C neutralization significantly repressed the expression of downstream pro-inflammatory cytokines, inflammatory cell infiltration, and Th17/IL-17A activation both in mice with renal IRI and DN. Mechanistical studies demonstrated that hypoxia or high glucose-induced IL-17C up-regulation was predominantly mediated by NF-κB pathway. INTERPRETATION: IL-17C participates in the pathogenesis of AKI and DN and inhibition of IL-17C shows potential as a therapeutic strategy for AKI and DN. FUNDING: The National Natural Science Foundation of China (81770741, 81700601 and 81870504).
Asunto(s)
Lesión Renal Aguda , Nefropatías Diabéticas , Interleucina-17 , Insuficiencia Renal Crónica , Daño por Reperfusión , Animales , Masculino , Ratones , Lesión Renal Aguda/patología , Albuminuria/complicaciones , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Citocinas/metabolismo , Nefropatías Diabéticas/metabolismo , Inflamación/patología , Interleucina-17/genética , Interleucina-17/metabolismo , Riñón/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/complicaciones , Daño por Reperfusión/patologíaRESUMEN
OBJECTIVE: We want to know the causes of AKI in oncology patients, including disease-related complications and the nephrotoxicity of chemotherapy drugs, in order to provide more useful clinical information. METHODS: In this review, an electronic search of the English language literature was performed in the database PubMed, with the results enriched by manual searches and citation mining, factors investigated in the selected articles included acute kidney injury, oncology, chemotherapy, anticancer drug, antitumor drug. RESULTS: According to the searched articles, we summarized the causes (including pre-renal, intrinsic renal, and post-renal lesion) of AKI in cancer patients and the corresponding management measures. Among the pre-renal factors we mainly described hypercalcemia, hematopoietic cell transplantation, post-renal factors we mainly described hemorrhagic cystitis, and intrinsic renal factors we mainly described thrombotic microangiopathy, chemotherapeutics, tumor lysis syndrome, cast nephropathy, in which the emphasis was on chemotherapy drug associated AKI and its treatment. CONCLUSIONS: AKI is not uncommon in cancer patients, and has diverse causes and negative outcomes. Both nephrologists and oncologists need to be aware of the unique reasons of AKI in this population and its optimal management.