Institut National de la Santé et de la Recherche Médicale U682, Equipe Cancer du Rein et Physiopathologie Rénale, Faculté de Médecine, 11 rue Humann, F-67085 Strasbourg, France.
Endocrinology. 2013 Feb;154(2):853-64. doi: 10.1210/en.2012-1802. Epub 2013 Jan 2.
Glomerulonephritis is characterized by the proliferation and apoptosis of mesangial cells (MC). The parathyroid-hormone related protein (PTHrP) is a locally active cytokine that affects these phenomena in many cell types, through either paracrine or intracrine pathways. The aim of this study was to evaluate the effect of both PTHrP pathways on MC proliferation and apoptosis. In vitro studies were based on MC from male transgenic mice allowing PTHrP-gene excision by a CreLoxP system. MC were also transfected with different PTHrP constructs: wild type PTHrP, PTHrP devoid of its signal peptide, or of its nuclear localization sequence. The results showed that PTHrP deletion in MC reduced their proliferation even in the presence of serum and increased their apoptosis when serum-deprived. PTH1R activation by PTHrP(1-36) or PTH(1-34) had no effect on proliferation but improved MC survival. Transfection of MC with PTHrP devoid of its signal peptide significantly increased their proliferation and minimally reduced their apoptosis. Overexpression of PTHrP devoid of its nuclear localization sequence protected cells from apoptosis without changing their proliferation. Wild type PTHrP transfection conferred both mitogenic and survival effects, which seem independent of midregion and C-terminal PTHrP fragments. PTHrP-induced MC proliferation was associated with p27(Kip1) down-regulation and c-Myc/E2F1 up-regulation. PTHrP increased MC survival through the activation of cAMP/protein kinase A and PI3-K/Akt pathways. These results reveal that PTHrP is a cytokine of multiple roles in MC, acting as a mitogenic factor only through an intracrine pathway, and reducing apoptosis mainly through the paracrine pathway. Thus, PTHrP appears as a probable actor in MC injuries.
肾小球肾炎的特征是系膜细胞（MC）的增殖和凋亡。甲状旁腺激素相关蛋白（PTHrP）是一种局部活性细胞因子，通过旁分泌或核内途径影响许多细胞类型的这些现象。本研究的目的是评估 PTHrP 两种途径对 MC 增殖和凋亡的影响。体外研究基于允许通过 CreLoxP 系统切除 PTHrP 基因的雄性转基因小鼠的 MC。还将不同的 PTHrP 构建体转染到 MC 中：野生型 PTHrP、无信号肽的 PTHrP 或无核定位序列的 PTHrP。结果表明，MC 中 PTHrP 的缺失减少了它们的增殖，即使在存在血清的情况下，也增加了它们在血清剥夺时的凋亡。PTH1R 激活通过 PTHrP(1-36)或 PTH(1-34)对增殖没有影响，但改善了 MC 的存活。转染缺乏信号肽的 PTHrP 显著增加了 MC 的增殖，同时最小程度地减少了它们的凋亡。缺乏核定位序列的 PTHrP 的过表达保护细胞免于凋亡，而不改变其增殖。野生型 PTHrP 转染赋予了有丝分裂和存活作用，这似乎与中间区域和 C 末端 PTHrP 片段无关。PTHrP 诱导的 MC 增殖与 p27(Kip1)下调和 c-Myc/E2F1 上调有关。PTHrP 通过激活 cAMP/蛋白激酶 A 和 PI3-K/Akt 途径增加 MC 的存活。这些结果表明，PTHrP 是 MC 中的一种多效细胞因子，仅通过核内途径作为有丝分裂因子起作用，并主要通过旁分泌途径减少凋亡。因此，PTHrP 似乎是 MC 损伤的一个可能的作用因子。
