Fluorofenidone protects against acute kidney injury

Abstract

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

“…Oxidative stress were measured via detecting ROS level, HG treatment induced the production of ROS as compared to the NG group whereas mefunidone reduced the level of ROS in HG‐induced SV40 MES‐13 cells (Figure 4C). Malondialdehyde (MDA) is a marker that reflects the levels of ROS 21 . In this study, mefunidone administration significantly decreased the elevation of MDA protein in kidney of both STZ rats and db/db mice (Figure 5D,E).…”

Self-developed NF-κB inhibitor 270 protects against LPS-induced acute kidney injury and lung injury through improving inflammation

“…In agreement with the histological renal morphology, compare with Veh group mice, plasma Crea and BUN levels were significantly increased in LPS-treated mice, and administration with 270 obviously restored LPS-triggered changes in a dose-dependent manner (Figure 6B). Neutrophil gelatinaseassociated lipocalin (NGAL) and kidney injury molecule 1 (KIM1) are specific tubular injury biomarkers (Jiang et al , 2019). As expected, the transcription levels of NGAL and KIM1 were dramatically enhanced in the kidneys after LPS exposure for up to 24 h, and pretreatment with 270 remarkably reversed renal anomalous mRNA expression of NGAL and KIM1 caused by the intraperitoneal administration of LPS (Figure 6C).…”

“…We discovered that 270 eliminated various pathological changes in renal and lung tissues, alleviated the enhanced of plasma Crea, BUN and pro-inflammation cytokines, and reversed the high expression of NGAL and KIM1 in kidney, accompanied by diminishing mRNA expression of proinflammation genes and blocking the activation of NF-κB and JNK signaling pathways in kidney and lung tissues. Beside, MPO is a biomarker of neutrophils and macrophages accumulation manifests severity of inflammation in tissues (Islam et al , 2019;Jiang et al , 2019), and 270 attenuated the elevated MPO activity in renal and lung tissues, indicating that 270 possess the anti-inflammation activity in vivo.…”

“…Myeloperoxidase (MPO) activity is a biochemical marker for the infiltration of neutrophils and macrophages. Malondialdehyde (MDA) is an indicator of oxidant stress (Jiang et al , 2019). MPO activity and MDA content were measured using a commercially available kit following manufacturer's instructions (Nanjing Jiancheng Bioengineering Institute).…”

“…Despite extensive efforts and substantial large-scale clinical trials have been made to develop effective therapeutic strategies for AKI and ALI. There are still no approved methods or agents to protect against AKI and ALI are available at present, which highlights the urgent require for the identifying novel pharmacological drugs for AKI and ALI (Zeng et al , 2017;Jiang et al , 2019).…”