Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice
Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice
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DOI：
10.2337/db14-1926
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发表时间：
2015-10-01
期刊：
影响因子：
7.7
通讯作者：
Gomez-Guerrero, Carmen
中科院分区：
文献类型：
--
作者：
Lazaro, Iolanda;Oguiza, Ainhoa;Gomez-Guerrero, Carmen
热休克蛋白（HSPs）是由细胞应激诱导的，作为分子伴侣调节蛋白质折叠。糖尿病损害许多HSP的功能/表达，包括HSP 70和HSP 90，它们是糖尿病并发症中涉及的病理机制的关键调节剂。因此，我们研究了药物HSP 90抑制是否改善糖尿病相关的肾损害和动脉粥样硬化进展的高血糖和高脂血症的小鼠模型（链脲佐菌素诱导的糖尿病载脂蛋白E缺陷小鼠）。用17-二甲氨基乙氨基-17-去甲氧基格尔德霉素（DMAG，2和4 mg/kg，10周）治疗糖尿病小鼠可改善肾功能，如蛋白尿、肾脏病变（系膜扩张、白细胞浸润和纤维化）以及促炎和促纤维化基因表达的剂量依赖性降低所证明。此外，DMAG显着减少动脉粥样硬化病变，并诱导更稳定的斑块表型，其特征在于较低的含量的脂质，白细胞和炎症标志物，并增加胶原和平滑肌细胞含量。从机制上讲，在糖尿病小鼠和高血糖和促炎条件下培养的细胞中，DMAG的肾保护和抗动脉粥样硬化作用是通过诱导保护性HSP 70沿着核因子-κ B（NF-κ B B）和信号转导和转录激活因子（STAT）以及靶基因表达的失活来介导的。总之，通过DMAG抑制HSP 90抑制实验性糖尿病肾脏和血管损伤的进展，具有预防糖尿病并发症的潜在意义。
Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kappa B (NF-kappa B) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.