Background

Our previous study suggested that palmitate (PA) induces human glomerular mesangial cells (HMCs) fibrosis. However, the mechanism is not fully understood. Recent studies suggested that transient receptor potential canonical channel 6 (TRPC6)/nuclear factor of activated T cell 2 (NFAT2) played an important role in renal fibrosis. Moreover, cluster of differentiation 36 (CD36) regulated the synthesis of TPRC6 agonist diglyceride. In the present study, we investigated whether PA induced HMCs fibrosis via TRPC6/NFAT2 mediated by CD36.

Methods

A type 2 diabetic nephropathy (DN) model was established in Sprague Dawley rats, and HMCs were stimulated with PA. Lipid accumulation and free fatty acid (FFA) uptake were measured. The expression levels of TGF-β1, p-Smad2/3, FN, TRPC6, NFAT2 and CD36 were evaluated. The intracellular calcium concentration ([Ca²⁺]i) was assessed.

Results

FFA were elevated in type 2 DN rats with kidney fibrosis in addition to NFAT2 and CD36 expression. In vitro, PA induced HMCs fibrosis, [Ca²⁺]_i elevation and NFAT2 activation. SKF96365 or TRPC6-siRNA could attenuate PA-induced HMCs damage. By contrast, the TRPC6 activator showed the opposite effect. Moreover, NFAT2-siRNA also suppressed PA-induced HMCs fibrosis. CD36 knockdown inhibited the PA-induced [Ca²⁺]_i elevation and NFAT2 expression. In addition, long-term treatment with PA decreased TRPC6 expression in HMCs.

Conclusion

The results of this study demonstrated that PA could induce the activation of the [Ca²⁺]_i/NFAT2 signaling pathway through TRPC6, which led to HMCs fibrosis. Although activation of TRPC6 attributed to CD36-mediated lipid deposition, long-term stimulation of PA may lead to negative feedback on the expression of TPRC6.

中文翻译：

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棕榈酸酯通过CD36介导的瞬时受体电位典型通道6 /活化T细胞2活化的核因子诱导人肾小球系膜细胞纤维化。

背景

我们先前的研究表明棕榈酸酯（PA）诱导人肾小球系膜细胞（HMCs）纤维化。但是，该机制尚未完全了解。最近的研究表明，瞬时受体潜在的规范性通道6（TRPC6）/激活的T细胞2（NFAT2）的核因子在肾纤维化中起重要作用。此外，分化簇36（CD36）调节了TPRC6激动剂甘油二酯的合成。在本研究中，我们调查了PA是否通过CD36介导的TRPC6 / NFAT2诱导HMCs纤维化。

方法

在Sprague Dawley大鼠中建立2型糖尿病肾病（DN）模型，并用PA刺激HMC。测量脂质积累和游离脂肪酸（FFA）摄取。评估TGF-β1，p-Smad2 / 3，FN，TRPC6，NFAT2和CD36的表达水平。评估细胞内钙浓度（[Ca ²⁺ ] i）。

结果

除NFAT2和CD36表达外，在患有肾纤维化的2型DN大鼠中，FFA升高。在体外，PA诱导HMCs纤维化，[Ca ²⁺ ] _i升高和NFAT2激活。SKF96365或TRPC6-siRNA可以减弱PA诱导的HMC损伤。相比之下，TRPC6激活剂显示相反的效果。此外，NFAT2-siRNA还抑制PA诱导的HMCs纤维化。CD36组合式抑制PA诱导的[Ca ²⁺ ] _i升高和NFAT2表达。此外，PA长期治疗可降低HMC中TRPC6的表达。

结论

这项研究的结果表明PA可以通过TRPC6诱导[Ca ²⁺ ] _i / NFAT2信号通路的激活，从而导致HMCs纤维化。尽管TRPC6的激活归因于CD36介导的脂质沉积，但是PA的长期刺激可能导致TPRC6表达的负反馈。