Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., Honolulu, HI, 96813, USA.
John A. Burns School of Medicine, University of Hawaii, 651 Ilalo St., Honolulu, HI, 96813, USA.
Sci Rep. 2020 Feb 11;10(1):2333. doi: 10.1038/s41598-020-59355-y.
TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.
TRPM7 属于瞬时受体电位 Melastatin 家族的离子通道，是一种与功能激酶融合的二价阳离子传导离子通道。TRPM7 在多种疾病中发挥关键作用，包括缺血性神经元死亡、癌症、心房颤动、疟疾入侵。TRPM7 在肺、肝和心脏纤维化中过度表达。在肾缺血再灌注后，即导致肾损伤和纤维化的事件后，TRPM7 也过度表达。然而，TRPM7 在肾纤维化中的作用尚不清楚。我们使用单侧输尿管梗阻（UUO）小鼠模型，研究了 TRPM7 是否有助于进行性肾脏损伤和纤维化。我们发现 TRPM7 在 UUO 肾脏中的表达增加。已知的 TRPM7 抑制剂 NS8593 的全身应用可防止 UUO 肾脏的肾萎缩，保留管状形成，并将 TRPM7 表达降低至正常水平。在 UUO 肾脏中，NS8593 处理可减少肾小管上皮细胞和间质细胞的细胞增殖，以及 TGF-β1/Smad 信号事件。我们得出结论，TRPM7 在炎症性肾损伤期间上调，并提出针对 TRPM7 的药物干预可能在进行性肾纤维化中具有保护作用。
