Abstract
Trichosanthes kirilowii lectin (TKL) has been reported to exert hypoglycemic effects in alloxan-induced diabetic mice. However, there is no evidence showing that it helps to prevent diabetic nephropathy (DN). We used a high glucose (HG)-induced HK-2 cell model and a streptozocin (STZ)-induced Wistar rat model to investigate the effects of TKL on DN, as well as the mechanisms for those effects. Our results showed that TKL significantly increased the viability of HG-treated HK-2 cells and inhibited cell apoptosis. In vivo experiments demonstrated that TKL attenuated STZ-induced histopathological damage and the inflammatory response in rat kidney tissues. Pre-treatment of HK-2 cells or STZ-treated rats with polyinosinic acid (Poly IC), an inhibitor of lectin-like oxLDL receptor 1 (LOX1), blocked the protective effect of TKL against HG- or STZ-induced damage to kidney tissue, indicating that TKL might exert its effect via LOX1-mediated endocytosis. Additional results suggested that TKL inhibits the phosphorylation of IκB kinase β (IKKβ) and the nuclear factor-κB (NF-κB) inhibitor protein (IκBα), and thereby reduces the nuclear translocation of NF-κB (p65). ChIP assay data indicated that TKL markedly inhibits the binding of p65 to the CASP9 gene in HG-treated HK-2 cells, subsequently suppressing transcription of the CASP9 gene. In the dual-luciferase reporter assay, TKL significantly inhibited luciferase activity in cells co-transfected with p65 and a wild-type capase-9 construct instead of mutated caspase-9 constructs.Taken together, our results show that TKL helps to protect against DN by inhibiting the LOX1/NF-κB/caspase-9 signaling pathway, suggesting TKL as a promising agent for treating DN.
Highlights
According to the latest World Health Organization (WHO) report, the number of diabetes mellitus (DM) patients has reached 347 million worldwide, and 114 million of those patients are in China [1]
These results indicated that HK-2 cells were not adversely affected by a Trichosanthes kirilowii lectin (TKL) concentration
We tested the effects of TKL on high glucose (HG)-treated HK-2 cells (Figure 1B) and found that their viability was decreased by treatment with 30 mM HG for 24, 48, or 72 h
Summary
According to the latest World Health Organization (WHO) report, the number of diabetes mellitus (DM) patients has reached 347 million worldwide, and 114 million of those patients are in China [1]. Diabetic nephropathy (DN) is a serious microvascular complication of DM characterized by initial proteinuria and increased creatinine levels [2]. The incidence of DN is growing at an alarming rate, and DN has become a worldwide public health problem [3]. The American Diabetes Association reported that 20–40% of patients with type 2 DM will develop DN-related complications ∼10 years after their initial diagnosis of DM [4,5]. Among patients who begin receiving renal replacement therapy (RRT), which greatly increases medical costs, the proportion of patients with DN ranges from 24 to 51% [6]. It has become essential to increase our understanding of the pathogenesis of DN
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