The renin inhibitor aliskiren attenuates high-glucose induced extracellular matrix synthesis and prevents apoptosis in cultured podocytes.
The renin inhibitor aliskiren attenuates high-glucose induced extracellular matrix synthesis and prevents apoptosis in cultured podocytes.
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肾素抑制剂阿利吉仑可减弱高葡萄糖诱导的细胞外基质合成并防止培养的足细胞凋亡。
DOI：
10.1159/000322242
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Adler,SharonG
中科院分区：
文献类型：
--
作者：
Phillips,LynettaM;Wang,Ying;Dai,Tiane;Feldman,DavidL;LaPage,Janine;Adler,SharonG
背景/目的细胞外基质（ECM）重塑和足细胞凋亡是糖尿病肾病（DN）的特征。Aliskiren （ALI）抑制肾素催化的血管紧张素原向血管紧张素i的转化。本研究测试了ALI对体外高糖环境下足细胞ECM增生和存活的影响。方法条件永生化小鼠足细胞在正常葡萄糖（NG; 5.5 mM）或高糖（HG; 40 mM）中孵育24-48 h，加不加ALI （20 nM）。实时荧光定量pcr检测纤维连接蛋白（FN）、胶原α5 （IV型）（Cola5IV）、基质金属蛋白酶2和9 （MMP2和MMP9）、金属蛋白酶组织抑制剂1和2 （TIMP1和TIMP2）。Western blot检测FN、Cola5IV、MMP2、MMP9、TIMP1和cleaved (activated) caspase-3。结果sali显著降低FN、Cola5IV和TIMP1 mRNA和蛋白水平，显著降低TIMP2和cleaved caspase-3 mRNA和蛋白水平。在HG条件下，ALI对MMP2 mRNA、蛋白和MMP9 mRNA均无影响。在NG条件下，ALI对FN、Cola5IV、MMP2、MMP9和活化的caspase-3蛋白均无影响。在HG条件下培养的足细胞中，通过TUNEL染色观察到ALI降低了活化的caspase-3蛋白和凋亡证据。结论ALI抑制肾素可减轻HG对培养足细胞的促纤维化和凋亡作用。这些数据加强了肾素抑制与ALI的治疗原理，超出了它的血流动力学效应。
Background/AimsAltered extracellular matrix (ECM) remodeling and podocyte apoptosis are characteristic features of diabetic nephropathy (DN). Aliskiren (ALI) inhibits the renin-catalyzed conversion of angiotensinogen to angiotensin I. This study tested ALI’s effect on podocyte ECM accretion and survival in a high-glucose environment in vitro.MethodsConditionally immortalized mouse podocytes were incubated in normal glucose (NG; 5.5 mM) or high glucose (HG; 40 mM) for 24–48 h with and without ALI (20 nM). Real-time RT-PCR was performed for fibronectin (FN), collagen α5 (type IV)(Cola5IV), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), and tissue inhibitor of metalloproteinases 1 and 2 (TIMP1 and TIMP2). Western blots were performed for FN, Cola5IV, MMP2, MMP9, TIMP1 and cleaved (activated) caspase-3.ResultsALI significantly reduced the mRNA and protein levels of FN, Cola5IV and TIMP1, and the mRNA of TIMP2 and cleaved caspase-3. ALI had no effect on MMP2 mRNA or protein or MMP9 mRNA tested under HG conditions. Under NG conditions, ALI had no effect on FN, Cola5IV, MMP2, MMP9 and activated caspase-3 proteins. ALI decreased the activated caspase-3 protein and evidence of apoptosis by TUNEL staining observed in podocytes cultured under HG conditions.ConclusionThese results show for the first time that renin inhibition with ALI mitigates the profibrotic and apoptotic effects of HG in cultured podocytes. These data strengthen the therapeutic rationale for renin inhibition with ALI beyond its hemodynamic effects.