Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
Int J Biol Sci. 2021 Jul 31;17(13):3343-3355. doi: 10.7150/ijbs.61274. eCollection 2021.
Mesangial cell (MC) proliferation and matrix expansion are basic pathological characteristics of IgA nephropathy (IgAN). However, the stepwise mechanism of MC proliferation and the exact set of related signaling molecules remain largely unclear. In this study, we found a significant upregulation of miR-214-3p in the renal cortex of IgAN mice by miRNA sequencing. hybridization analysis showed that miR-214-3p expression was obviously elevated in MCs in the renal cortex in IgAN. Functionally, knockdown of miR-214-3p alleviated mesangial hypercellularity and renal lesions in IgAN mice. , the inhibition of miR-214-3p suppressed MC proliferation and arrested G1-S cell cycle pSrogression in IgAN. Mechanistically, a luciferase reporter assay verified PTEN as a direct target of miR-214-3p. Downregulation of miR-214-3p increased PTEN expression and reduced p-JNK and p-c-Jun levels, thereby inhibiting MC proliferation and ameliorating renal lesions in IgAN. Moreover, these changes could be attenuated by co-transfection with PTEN siRNA. Collectively, these results illustrated that miR-214-3p accelerated MC proliferation in IgAN by directly targeting PTEN to modulate JNK/c-Jun signaling. Therefore, miR-214-3p may represent a novel therapeutic target for IgAN.
系膜细胞（MC）增殖和基质扩张是 IgA 肾病（IgAN）的基本病理特征。然而，MC 增殖的逐步机制和确切的相关信号分子集在很大程度上仍不清楚。在这项研究中，我们通过 miRNA 测序发现 IgAN 小鼠肾脏皮质中 miR-214-3p 显著上调。杂交分析显示，IgAN 中肾脏皮质 MC 中 miR-214-3p 的表达明显升高。功能上，miR-214-3p 的敲低减轻了 IgAN 小鼠系膜细胞的过度增生和肾脏病变。此外，抑制 miR-214-3p 抑制了 IgAN 中 MC 的增殖，并阻滞了 G1-S 细胞周期进展。在机制上，荧光素酶报告基因实验验证了 PTEN 是 miR-214-3p 的直接靶标。miR-214-3p 的下调增加了 PTEN 的表达，降低了 p-JNK 和 p-c-Jun 的水平，从而抑制了 IgAN 中的 MC 增殖并改善了肾脏病变。此外，这些变化可以通过共转染 PTEN siRNA 来减弱。总之，这些结果表明，miR-214-3p 通过直接靶向 PTEN 来调节 JNK/c-Jun 信号通路，从而加速 IgAN 中的 MC 增殖。因此，miR-214-3p 可能成为 IgAN 的一种新的治疗靶点。
