Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway.
Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway.
复制标题
DOI：
10.1038/cddis.2015.125
复制
发表时间：
2015-05-07
影响因子：
9
通讯作者：
Lehtonen S
中科院分区：
文献类型：
--
作者：
Saurus P;Kuusela S;Lehtonen E;Hyvönen ME;Ristola M;Fogarty CL;Tienari J;Lassenius MI;Forsblom C;Lehto M;Saleem MA;Groop PH;Holthöfer H;Lehtonen S
正常白蛋白尿的1型糖尿病（T1 D）患者血清脂多糖（LPS）活性升高可预测糖尿病肾病（DN）的进展，但其背后的机制尚不清楚。我们观察到，用正常白蛋白尿T1 D患者的血清治疗培养的人足细胞，LPS活性高，下调3-磷酸肌醇依赖性激酶1（PDK 1），Akt细胞存活途径的激活剂，并诱导细胞凋亡。在培养的人足细胞中PDK 1的敲低抑制抗凋亡Akt途径，刺激促凋亡p38 MAPK途径，并增加细胞凋亡，证明PDK 1在足细胞中的抗凋亡作用。有趣的是，PDK 1在糖尿病大鼠和2型糖尿病患者的肾小球中在蛋白尿发作之前下调，进一步表明PDK 1的表达减少与足细胞损伤和DN的发展相关。在体外和小鼠体内用LPS处理足细胞降低PDK 1表达并诱导细胞凋亡，这通过用免疫调节剂GIT 27抑制Toll样受体（TLR）信号通路来防止。我们的数据显示，LPS下调细胞存活因子PDK 1并诱导足细胞凋亡，并且用GIT 27阻断TLR通路可能提供一种非肾毒性的手段来预防DN的进展。
High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.