Translational research : the journal of laboratory and clinical medicine
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Substantial evidence suggests that the intrarenal renin-angiotensin system (RAS) plays a role in the pathogenesis of diabetic nephropathy. Although the glomerular RAS is activated in the streptozotocin (STZ)-diabetic rat, the status of the glomerular RAS in the Zucker diabetic fatty (ZDF) rat, which is a commonly used genetic model of diabetes, is not known. Angiotensinogen (AGT), angiotensin II (Ang II), angiotensin converting enzyme (ACE), and angiotensin converting enzyme 2 (ACE2) were measured in glomeruli isolated from 4-week-old STZ-diabetic rats and 32-week-old ZDF rats. ⋯ ACE levels were not affected by diabetes in either diabetic model. In conclusion, the glomerular RAS is activated in the STZ diabetic rat but not in the ZDF rat despite a similar degree of hyperglycemia. The mechanism of nephropathy in the ZDF rat may involve factors other than hyperglycemia and RAS activation, such as hypertension and hyperlipidemia.
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The integration of molecular, genomic, and clinical medicine in the post-genome era provides the promise of novel information on genetic variation and pathophysiologic cascades. The current challenge is to translate these discoveries rapidly into viable biomarkers that identify susceptible populations and into the development of precisely targeted therapies. ⋯ Our search for candidate genes, which are gene variations that drive susceptibility to and severity of enigmatic acute and chronic lung disorders, provides a logical framework to understand better the evolution of genomic medicine. The dissection of the genetic basis of complex diseases and the development of highly individualized therapies remain lofty but achievable goals.
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We hypothesize that pulmonary arterial hypertension (PAH)-associated genes identified by expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with idiopathic pulmonary arterial hypertension (IPAH) can also be identified in PBMCs from scleroderma patients with PAH (PAH-SSc). Gene expression profiles of PBMCs collected from IPAH (n = 9), PAH-SSc (n = 10) patients, and healthy controls (n = 5) were generated using HG_U133A_2.0 GeneChips and were processed by the RMA/GCOS_1.4/SAM_1.21 data analysis pipeline. Disease severity in consecutive patients was assessed by functional status and hemodynamic measurements. ⋯ These data demonstrate that PBMCs from patients with PAH-SSc carry distinct transcriptional expression. Furthermore, our findings suggest an association between angiogenesis-related gene expression and severity of PAH in PAH-SSc patients. Deciphering the role of genes involved in vascular remodeling and PAH development may reveal new treatment targets for this devastating disorder.