Prostacyclin is one of a number of lipid mediators elaborated from the metabolism of arachidonic acid by the cyclooxygenase (COX) enzymes. This prostanoid is a potent inhibitor of platelet aggregation, and its production by endothelial cells and protective role in the vasculature are well established. In contrast, much less is known regarding the function of this prostanoid in other disease processes. We show here that COX-2-dependent production of prostacyclin plays an important role in the development of fibrotic lung disease, limiting both the development of fibrosis and the consequential alterations in lung mechanics. In stark contrast, loss of prostaglandin E(2) synthesis and signaling through the G(s)-coupled EP2 and EP4 receptors had no effect on the development of disease. These findings suggest that prostacyclin analogs will protect against bleomycin-induced pulmonary fibrosis in COX-2(-/-) mice. If such protection is observed, investigation of these agents as a novel therapeutic approach to pulmonary fibrosis in humans may be warranted.
Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT 1 ) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Fas lpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT 1A ); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT 1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT 1A -deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT 1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT 1B , and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT 1A -deficient lpr mice, and they showed evidence of exaggerated AT 1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT 1A -deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.
PGx testing provides significant 'real world' cost savings, while simultaneously improving adherence in a difficult to treat psychiatric population. Limitations of this study include the lack of therapeutic efficacy follow-up data and possible confounding due to matching only on demographic and psychiatric variables.
Abstract-Vascular injury and remodeling are common pathological sequelae of hypertension. Previous studies have suggested that the renin-angiotensin system acting through the type 1 angiotensin II (AT 1 ) receptor promotes vascular pathology in hypertension. To study the role of AT 1 receptors in this process, we generated mice with cell-specific deletion of AT 1 receptors in vascular smooth muscle cells using Key Words: angiotensin II Ⅲ hypertrophy Ⅲ hyperplasia Ⅲ aorta Ⅲ smooth muscle Ⅲ hypertension T he renin-angiotensin system (RAS) is a principal regulator of blood pressure homeostasis; dysregulation of this system commonly contributes to human hypertension. 1,2 Accordingly, pharmacological inhibitors of the RAS, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, can effectively lower blood pressure in a significant proportion of patients with essential hypertension. 3,4 Moreover, these agents also attenuate end-organ damage, decreasing cardiovascular morbidity, and slowing the progression of chronic kidney injury. 5,6 It has been suggested that RAS inhibitors provide protection against complications of hypertension beyond their effects to lower blood pressure, indicating nonhemodynamic, cellular actions of angiotensin II to promote tissue damage. 7 However, in some clinical trials, end-organ protection by RAS inhibition has been accompanied by more effective reduction of blood pressure. 4,8,9 Moreover, studies in animal models have suggested that the antihypertensive actions of RAS inhibitors are critical for preventing cardiac hypertrophy 10 and progressive kidney injury. 11 The vascular system is a major target of damage in hypertension. Expansion of arteries and arterioles in the kidney, also called nephrosclerosis, is the most common renal pathological lesion accompanying hypertension 12 and is an important cause of chronic kidney disease in blacks. 13 Vessel remodeling with changes in compliance is also seen in the aorta and other vascular beds in hypertension, 14 in which the RAS has potent actions to influence vascular structure and function. 15 For example, angiotensin II causes systemic vasoconstriction by activa-
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