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The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts (1,2). Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed [...]

Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt sensitivity and for hypertension in hydronephrosis. Hydronephrosis was induced in superoxide dismutase 1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko), and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high-sodium (4% NaCl) diets and with chronic tempol supplementation. The 8-iso-prostaglandin-[F.sub.2[alpha]] (F2-IsoPs) and protein excretion profiles and renal histology were investigated. The acute effects of tempol on blood pressure and TGF were studied in rats. In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114 [+ or -] 1 to 120 [+ or -] 2 mmHg), which was augmented in SOD1-ko (125 [+ or -] 3 to 135 [+ or -] 4 mmHg) but abolished in SOD1-tg (109 [+ or -] 3 to 108 [+ or -] 3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108 [+ or -] l to 115 [+ or -] 2 mmHg), which was not found in wild types or SOD1-tg. Chronic tempol treatment reduced blood pressure in SOD1-ko controls (-7 mmHg) and in hydronephrotic wild-type (-8 mmHg) and SOD1-ko mice (-16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-type were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis [[DELTA][P.sub.sF]: 15.2 [+ or -] 1.2 to 9.1 [+ or -] 0.6 mmHg, turning point: 14.3 [+ or -] 0.8 to 19.7 [+ or -] 1.4 nl/min]. Oxidative stress due to SOD1 deficiency causes salt sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension. blood pressure; CuZnSOD; isoprostanes; superoxide; telemetry; tempol; tubuloglomernlar feedback; ureteral obstruction; oxidative stress

Platelet-derived growth factor (PDGF)-BB is a well-known smooth muscle (SM) cell (SMC) phenotypic modulator that signals by binding to PDGF [alpha][alpha]-, [alpha][beta]-, and [beta][beta]-membrane receptors. PDGF-DD is a recently identified PDGF family member, and its role in SMC phenotypic modulation is unknown. Here we demonstrate that PDGF-DD inhibited expression of multiple SMC genes, including SM [alpha]-actin and SM myosin heavy chain, and upregulated expression of the potent SMC differentiation repressor gene Kruppel-like factor-4 at the mRNA and protein levels. On the basis of the results of promoter-reporter assays, changes in SMC gene expression were mediated, at least in part, at the level of transcription. Attenuation of the SMC phenotypic modulatory activity of PDGF-DD by pharmacological inhibitors of ERK phosphorylation and by a small interfering RNA to Kruppel-like factor-4 highlight the role of these two pathways in this process. PDGF-DD failed to repress SM [alpha]-actin and SM myosin heavy chain in mouse SMCs lacking a functional PDGF [beta]-receptor. Importantly, PDGF-DD expression was increased in neointimal lesions in the aortic arch region of apolipoprotein C-deficient ([ApoE.sup.-/-]) mice. Furthermore, human endothelial cells exposed to an atherosclerosis-prone flow pattern, as in vascular regions susceptible to the development of atherosclerosis, exhibited a significant increase in PDGF-DD expression. These findings demonstrate a novel activity for PDGF-DD in SMC biology and highlight the potential contribution of this molecule to SMC phenotypic modulation in the setting of disturbed blood flow. shear stress; disturbed blood flow; smooth muscle myosin heavy chain; smooth muscle [alpha]-actin

Thrombolytic treatment of ischemic stroke with tissue plasminogen activator (tPA) is markedly limited owing to concerns about hemorrhagic complications and the requirement that tPA be administered within 3 h of symptoms. Here we report that tPA activation of latent platelet-derived growth factor-CC (PDGF-CC) may explain these limitations. Intraventricular injection of tPA or active PDGF-CC, in the absence of ischemia, leads to significant increases in cerebrovascular permeability. In contrast, co-injection of neutralizing antibodies to PDGF-CC with tPA blocks this increased permeability, indicating that PDGF-CC is a downstream substrate of tPA within the neurovascular unit. These effects are mediated through activation of PDGF-a receptors (PDGFR-[alpha]) on perivascular astrocytes, and treatment of mice with the PDGFR-[alpha] antagonist imatinib after ischemic stroke reduces both cerebrovascular permeability and hemorrhagic complications associated with late administration of thrombolytic tPA. These data demonstrate that PDGF signaling regulates blood-brain barrier permeability and suggest potential new strategies for stroke treatment., Stroke is a leading cause of adult morbidity and mortality (1). Ischemic stroke is the most common form of stroke and occurs when there is an abrupt interruption of blood [...]

Although studies have suggested a role for angiogenesis in determining heart size during conditions demanding enhanced cardiac performance, the role of EC mass in determining the normal organ size is [...]