Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms
Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms
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DOI：
10.1681/asn.2004110915
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发表时间：
2005-11-01
影响因子：
13.6
通讯作者：
Makino, H
中科院分区：
文献类型：
--
作者：
Baba, M;Wada, J;Makino, H
半乳糖凝集素是与β -半乳糖苷结合的凝集素，参与多种生物过程，如细胞凋亡、细胞增殖和细胞周期调节。半乳糖凝集素-9 （Galectin-9, Gal-9）在小鼠胸腺细胞中具有凋亡潜能，在肾毒性血清肾炎模型中具有活化CD8(+) T细胞的作用。在这项研究中，Gal-9对早期糖尿病肾病的标志性病理变化之一g1期细胞周期阻滞的影响进行了研究。8周龄雄性db/db小鼠分别注射重组Gal-9或载体8周。在db/db小鼠体内注射Gal-9可显著抑制肾小球肥大和系膜基质扩张，减少尿白蛋白排泄。Gal-9降低肾小球中tgf - β 1的表达以及肾小球中p27(Kip1)-和p21(Cip1)-阳性细胞的数量。肾素和IV型胶原双染色显示足细胞主要呈p27（kip1）阳性。为了进一步证实Gal-9对细胞周期的调节作用，我们将条件永生化的小鼠足细胞分别培养在含有Gal-9的5.5和25 MM d -葡萄糖下。细胞周期分布分析显示，Gal-9维持了细胞周期从G1期开始的进一步进展。Gal-9逆转高糖介导的p27（Kip1）和p21（Cip1）的上调，抑制细胞周期依赖性肥大，即减少[H-3]脯氨酸的掺入。这些数据表明，Gal-9通过抑制肾小球tgf - β 1的表达和抑制细胞周期蛋白依赖性激酶抑制剂，在诱导它们从G1期成功进展到G2期中起着核心作用。Gal-9可能会推动新的治疗工具的开发。糖尿病肾病。
Galectins are beta-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CD8(+) T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on G1-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-beta 1 and the number of p27(Kip1)- and p21(Cip1)-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27(kip1). For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 MM D-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27(Kip1) and p21(Cip1) and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [H-3]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-beta 1 and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward. diabetic nephropathy.