Thomas Coffman

..Accordingly, these studies identify PGE(2)/EP(3) as a proinflammatory signaling pathway that promotes mast cell activation...

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..Thus, among the strains and models tested, the DBA/2 genetic background and the Akita (Ins2(+/C96Y)) model may be the most useful platforms for model development...

..Our data suggest that adjuvant therapy that blocks unrestrained Tx actions might protect against end-organ damage without affecting blood pressure in patients taking COX-2 inhibitors...

..Thus, TP receptors in vascular smooth muscle cells play a major role in mediating the actions of thromboxane A(2) in TP agonist-induced shock, hypertension, and vascular remodeling of the aorta...

..The intent of this review is to provide a sense of where the field is progressing, with an emphasis on work that sheds light on pathogenic mechanisms and that is therefore likely to inform new translational advances...

..In summary, these results demonstrate that AT(1A) receptors in epithelial cells of the collecting duct directly modulate aquaporin-2 levels and contribute to the concentration of urine...

..Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney...

..However, irrespective of genetic background, the TP receptor makes a robust contribution to the pathogenesis of angiotensin II-dependent hypertension...

..Thus, the regulation of blood pressure by the RAS is mediated by AT(1) receptors both within and outside the kidney...

..01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury...

..These data indicate that genetic background significantly modifies the BP response to mPGES1 deficiency. Exaggerated production of thromboxane may contribute to the robust hypertension and albuminuria in 129 mPGES1-deficient mice...

..Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure...

..These findings, with previous experiments, clearly establish the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications...

..Thus, vascular AT(1A) receptors promote oxidative stress in the aortic wall but are not required for remodeling in angiotensin II-dependent hypertension...

..These data support a critical role for the renal epithelium and/or vasculature as the final determinants of the intra-arterial pressure in hypertension...

..By 2-point analysis, we found a region spanning 5 cM on chromosome 3, with significant linkage to the development of renal vascular lesions (LOD score: 3.3 to 3.8)...

..001), a level virtually identical to that of the wild-type controls. These data suggest that the XT2 orphan transporter is involved in glycine reabsorption and that the absence of this transporter is sufficient to cause hypertension...

..Identification of these naturally occurring strain differences should prove useful for nephropathy modeling and may be exploited to allow identification of novel susceptibility alleles for albuminuria in diabetes...

..These findings, together with previous experiments, confirm the kidney's critical role in the pathogenesis of hypertension and its complications...

..CONCLUSIONS: AT1 receptors play an important role in the development of fibrosis. Pharmacological blockade of AT1 receptors appears to be a promising approach to treat liver fibrosis...

..These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy...

..However, the nature and relative contributions of these actions may differ in hypertension...

..In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype...

..We provide a general review of the RAS and its role in diabetic nephropathy...

..It is speculated that Galpha q-coupled signaling cascades may be important effector pathways mediating renal injury...

..Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF...

..Thus, Rho GTPases acting through Rho kinase play a unique role in T cell activation during cellular immune responses by promoting structural rearrangements that are critical for T cell signaling...

..Since AT1A-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...

..The impact of enhanced AT1 receptor expression on blood pressure may be blunted by systemic compensatory responses and altered signal-effector coupling in the vasculature...

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..Abrogation of these responses is associated with improved graft survival and reduced CR in MHC-/- grafts...

..Such ligands may have potential as a novel class of therapeutic agents...

..Specific inhibition of the TP receptor may provide a more precise approach to limit inflammation without some of the untoward effects associated with NSAIDs...

..Together, our findings illustrate a sex-specific role for CYP2J5 in regulation of blood pressure, proximal tubular transport, and afferent arteriolar responsiveness via an estrogen-dependent mechanism...

..Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function...

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..cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA(2) may result in novel therapeutic targets for a disease with limited treatment options...

..This discovery suggests a distinct pathway for activation of the RAS that may have a particular impact on the pathogenesis of chronic tissue injury as well as more acute pathology such as arrhythmias in the heart...

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..A new study suggests that PGI2 plays a critical role in stimulating renin release and promoting hypertension following renal artery stenosis...

..Surprisingly, mPGES1 or mPGES2 are not required, suggesting other alternative mechanisms for generating PGE(2) in response to macula densa stimulation...

..These studies indicate that TXA(2) mediates a portion of apoptotic thymocyte death caused by LPS. The absence of an effect of global inhibition of prostanoid synthesis suggests a complex role for prostanoids in this model...

..Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity...

..In this review, we will highlight studies using this approach to uncover new perspectives on the physiology of the renin-angiotensin system...

..These findings provide a clear rationale for specifically targeting proteinuria in pharmacologic interventions of chronic nephropathies...

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..These results support the essential role of AT1A receptors in mediating 2K1C hypertension and support the hypothesis that augmented NO production serves as a counteracting system in this model of hypertension...

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..Further work is necessary to explore the potential mechanisms underlying these gender-based differences...

..This functional cascade requires modulation of agonist-induced calcium transient by EGFR and PI3K with extremely fast kinetics, suggesting a novel paradigm for GPCR-mediated calcium signaling, which may offer future therapeutic targets...

..This approach allows for the rapid screening for ACE2, which has applications in drug testing, high-throughput enzymatic assays, and identification of novel substrates/inhibitors of the renin-angiotensin system...

..Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans...

..Cell lines were amplified, yielding a virtually unlimited supply of highly differentiated, transport-competent, angiotensin receptor-deficient PCT cell lines...

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..Our data suggest a marked divergence of renin and Cox-2 expression in the kidney cortex of C57Bl/6 mice with no clear evidence for a role of Cox-2-derived prostanoids from the macula densa in the regulation of renin expression...

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..Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA2 in other organ systems...

..These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors...

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..This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2...

..abstract_text> ..

..Completion of this program should allow trainees to pursue careers as academicians conducting high-quality research in clinical and basic aspects of nephrology ..

..3. To define the consequences of altered angiogenic signaling on the development of albuminuria and nephropathy in diabetes. ..

..To identify the genes in the PGE2 pathway controlling renin expression and release. 2. To define the capacity of mPGE synthases to modulate kidney function. 3. To define the impact of PGE2 metabolism by 15-PGDH on renal functions. ..

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..To identify the genes in the PGE2 pathway controlling renin expression and release. 2. To define the capacity of mPGE synthases to modulate kidney function. 3. To define the impact of PGE2 metabolism by 15-PGDH on renal functions. ..

..Specific Aim V: To define the contribution of the AgtrlB gene to blood pressure regulation, mice with targeted disruption of the AgtrlB gene will be studied. ..

..These studies will define the physiological importance of AT1 receptor signaling in the kidney and will compare the relative contribution of epithelial and vascular actions of AT1 receptors in regulating blood pressure. ..

..We plan to share these technologies fully with other investigators to help accomplish the overall goals of the Mouse Models of Diabetic Complications Consortium. ..

..We will explore the mechanism used by the EP4 receptor to raise blood pressure and will define its potential utility as a therapeutic target for the treatment of hypertension. ..