Background/Aim: Endothelial dysfunction due to reduced nitric oxide (NO) availability precedes the development of atherosclerosis. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is not only a cause of endothelial dysfunction, but also a predictor of the cardiovascular outcome in end-stage renal disease (ESRD) patients on hemodialysis (HD). α-Lipoic acid (ALA), a strong antioxidant, increases NO-mediated vasodilation in diabetic patients. We investigated whether ALA could decrease the plasma level of ADMA in diabetic ESRD patients on HD. Methods: Fifty patients undergoing HD three times per week were randomized to a treatment group receiving ALA 600 mg/day for 12 weeks or a control group. We measured the plasma levels of cholesterol, albumin, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, hemoglobin A1c, and ADMA in both groups at baseline and at 12 weeks. Results: In the control group, the levels of total cholesterol, serum albumin, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, hemoglobin A1c, and ADMA did not change. In the treatment group, the plasma levels of ADMA decreased significantly from a median of 1.68 (range 0.45–3.78) µM to a median of 1.31 (range 0.25–3.19) µM (p = 0.001). Conclusion: Considering that ADMA is an independent risk factor for cardiovascular outcome in ESRD patients, ALA may have the potential of a beneficial effect in them, in part by decreasing the plasma level of ADMA.
The epithelial-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress induced by urinary protein, particularly albumin, play an important role in tubulointerstitial injury. However, signaling pathways regulating both albumin-induced EMT and ER stress are not precisely known. We postulated that reactive oxygen species (ROS), c-Src kinase, and mammalian target of rapamysin (mTOR) would act as upstream signaling molecules. We further examined the effect of imatinib mesylate on these processes. All experiments were performed using HK-2 cells, a human proximal tubular cell line. Protein and mRNA expression were measured by Western blot analysis and real-time PCR, respectively. Exposure of tubular cells to albumin (5 mg/ml) for up to 5 days induced EMT in a time-dependent manner, as shown by conversion to the spindle-like morphology, loss of E-cadherin protein, and upregulation of α-smooth muscle actin mRNA and protein. Albumin also induced ER stress as evidenced by phosphorylation of eukaryotic translation initiation factor-2α and increased expression of GRP78 mRNA and protein. Albumin induced ROS, c-Src kinase, and mTOR as well. Antioxidants, c-Src kinase inhibitor (PP2), and mTOR inhibitor (rapamycin) suppressed the albumin-induced EMT and ER stress. Antioxidants and PP2 inhibited the albumin-induced c-Src kinase and mTOR, respectively. Imatinib suppressed the albumin-induced EMT and ER stress via inhibition of ROS and c-Src kinase. Imatinib also inhibited the albumin-induced mRNA expression of MCP-1, VCAM-1, transforming growth factor (TGF)-β1, and collagen I (α1). In conclusion, the ROS-c-Src kinase-mTOR pathway played a central role in the signaling pathway that linked albumin to EMT and ER stress. Imatinib might be beneficial in attenuating the albumin-induced tubular injury.
Background: Endoplasmic reticulum (ER) stress induced by urinary albumin plays an important role in tubulointerstitial injury. We have shown that albumin-induced ER stress is regulated through reactive oxygen species (ROS)-c-Src kinase-mTOR signaling pathways. We postulated that peroxisome proliferator-activated receptor-γ (PPAR-γ) might also act as an upstream signaling molecule between c-Src kinase and mTOR. It has been suggested that AMP-activated protein kinase (AMPK) is involved in attenuation of ER stress. We examined whether and how activation of AMPK suppressed the albumin-induced ER stress and apoptosis in tubular epithelial cells. Method: HK-2 cells, a proximal tubular cell line, were used. Protein expressions were measured by Western blot analysis. Intracellular ROS and apoptosis were analyzed by flow cytometry. Results: Albumin-induced PPAR-γ expression and PPAR-γ inhibitor (GW9662) suppressed the albumin-induced ER stress. c-Src kinase inhibitor and GW9662 reduced the albumin-induced PPAR-γ and mTOR, respectively. Metformin (the best known clinical activator of AMPK) and another AMPK activator (AICAR) suppressed the albumin-induced ER stress via inhibition of ROS through induction of endogenous antioxidant thioredoxin. AMPK inhibitor blocked the effect of metformin and AICAR. Our in vivo animal study showed that metformin reduced the renal cortical expression of ER stress protein (GRP78) in protein-overload proteinuria rats. Metformin also reducedthe caspase 3-dependent apoptosis induced by albumin. Conclusion: PPAR-γ was involved in albumin-induced ER stress as an upstream signaling molecule between c-Src kinase and mTOR. AMPK activation might be beneficial in attenuating the tubulointerstitial injury induced by albumin.
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