Department of Nephrology, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Zhengzhou, 450014, China.
Inflammation. 2021 Aug;44(4):1416-1425. doi: 10.1007/s10753-021-01426-x. Epub 2021 Feb 18.
Lupus nephritis (LN) is a severe symptom of systemic lupus erythematosus and miR-21-5p is upregulated during LN. In the current study, the effects of pioglitazone (Pg), a peroxisome proliferator-activated receptor-γ (PPARγ) agonist, on LN development were assessed and explained by focusing miR-21-5p/TIMP3 axis. The expressions of miR-21-5p and PPARγ in LN mice were detected and then the mice were treated with pioglitazone to evaluate the anti-LN effects of agent. The miR-21-5p level was induced in MRL/lpr mice to confirm the central role of miR-21-5p inhibition in the protective effects of Pg against LN. The level of miR-21-5p was upregulated, while the level of PPARγ was downregulated in MRL/lpr mice. Pg inhibited miR-21-5p in renal tissues, which induced the expression of TIMP3. The changes in miR-21-5p/TIMP3 axis led to the improvements in renal structure and function, and inhibited autoimmune response. The induction of miR-21-5p impaired the effects of Pg, along with the suppression of TIMP3. The expression of miR-21-5p was associated with the progression of LN, contributing to the suppression of TIMP3 and development of LN. The inhibition of the miR-21-5p by Pg would restore the structure and function of kidneys in LN mice via the activation of PPARγ.
狼疮性肾炎（LN）是系统性红斑狼疮的严重症状，miR-21-5p 在 LN 期间上调。在本研究中，通过关注 miR-21-5p/TIMP3 轴，评估了过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂吡格列酮（Pg）对 LN 发展的影响，并对其作用机制进行了解释。检测了 LN 小鼠中 miR-21-5p 和 PPARγ 的表达，然后用吡格列酮对小鼠进行治疗，以评估该药物的抗 LN 作用。在 MRL/lpr 小鼠中诱导 miR-21-5p 水平以确认 miR-21-5p 抑制在 Pg 对 LN 的保护作用中的核心作用。MRL/lpr 小鼠中 miR-21-5p 水平上调，而 PPARγ 水平下调。Pg 在肾组织中抑制 miR-21-5p，诱导 TIMP3 的表达。miR-21-5p/TIMP3 轴的变化导致肾脏结构和功能的改善，并抑制自身免疫反应。miR-21-5p 的诱导削弱了 Pg 的作用，同时抑制了 TIMP3。miR-21-5p 的表达与 LN 的进展相关，导致 TIMP3 的抑制和 LN 的发展。Pg 通过激活 PPARγ 抑制 miR-21-5p，从而恢复 LN 小鼠肾脏的结构和功能。
