Vascular Fibrosis in Aging and Hypertension: Molecular Mechanisms and Clinical Implications

Hypertension is estimated to cause 4.5% of current global disease burden and is as prevalent in many developing countries, as in the developed world. Blood pressure-induced cardiovascular risk rises continuously across the whole blood pressure range. Countries vary widely in capacity for management of hypertension, but worldwide the majority of diagnosed hypertensives are inadequately controlled. This statement addresses the ascertainment of overall cardiovascular risk to establish thresholds for initiation and goals of treatment, appropriate treatment strategies for non-drug and drug therapies, and cost-effectiveness of treatment. Since publication of the WHO/ISH Guidelines for the Management of Hypertension in 1999, more evidence has become available to support a systolic blood pressure threshold of 140 mmHg for even 'low-risk' patients. In high-risk patients there is evidence for lower thresholds. Lifestyle modification is recommended for all individuals. There is evidence that specific agents have benefits for patients with particular compelling indications, and that monotherapy is inadequate for the majority of patients. For patients without a compelling indication for a particular drug class, on the basis of comparative trial data, availability, and cost, a low dose of diuretic should be considered for initiation of therapy. In most places a thiazide diuretic is the cheapest option and thus most cost effective, but for compelling indications where other classes provide additional benefits, even if more expensive, they may be more cost effective. In high-risk patients who attain large benefits from treatment, expensive drugs may be cost effective, but in low-risk patients treatment may not be cost-effective unless the drugs are cheap.

Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-beta1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-beta1-induced EMT. Because reactive oxygen species (ROS) are involved in TGF-beta1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-beta1-induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-beta1 (0.2 to 20 ng/ml) or H(2)O(2) (1 to 500 microM) in the presence or absence of antioxidants (N-acetylcysteine or catalase), inhibitors of NADPH oxidase (diphenyleneiodonium and apocynin), mitochondrial electron transfer chain subunit I (rotenone), and MAPK (PD 98059, an MEK [MAP kinase/ERK kinase] inhibitor, or p38 MAPK inhibitor) for up to 96 h. TGF-beta1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, alpha-smooth muscle actin (alpha-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-beta1-induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H(2)O(2) reproduced all of the effects of TGF-beta1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-beta1-induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-beta1- and H(2)O(2)-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-beta1-induced ROS. Thus, this data suggest that ROS play an important role in TGF-beta1-induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells.