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1.  THE IMPACT OF MICROSOMAL PROSTAGLANDIN E SYNTHASE 1 (mPGES1) ON BLOOD PRESSURE IS DETERMINED BY GENETIC BACKGROUND 
Hypertension  2010;55(2):531-538.
Prostaglandin (PG) E2 has multiple actions that may affect blood pressure. It is synthesized from arachidonic acid by the sequential actions of phospholipases, cyclooxygenases, and PGE synthases. While microsomal PGE synthase 1 (mPGES1) is the only genetically-verified PGE synthase, results of previous studies examining the consequences of mPGES1-deficiency on blood pressure (BP) are conflicting. To determine whether genetic background modifies the impact of mPGES1 on BP, we generated mPGES1−/− mice on two distinct inbred backgrounds, DBA/1lacJ and 129/SvEv. On the DBA/1 background, baseline BP was similar between wild-type (WT) and mPGES1−/− mice. By contrast, on the 129 background, baseline BPs were significantly higher in mPGES1−/− animals than WT controls. During angiotensin II infusion, the DBA/1 mPGES1−/− and WT mice developed mild hypertension of similar magnitude, while 129-mPGES1−/− mice developed more severe hypertension than WT controls. DBA/1 animals developed only minimal albuminuria in response to angiotensin II infusion. By contrast, WT 129 mice had significantly higher levels of albumin excretion than WT DBA/1 and the extent of albuminuria was further augmented in 129 mPGES1−/− animals. In WT mice of both strains, the increase in urinary excretion of PGE2 with angiotensin II was attenuated in mPGES1−/− animals. Urinary excretion of thromboxane was unaffected by angiotensin II in the DBA/1 lines but increased more than 4-fold in 129 mPGES1−/− mice. 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.
doi:10.1161/HYPERTENSIONAHA.109.145631
PMCID: PMC2836731  PMID: 20065147
prostanoids; PGE synthase; blood pressure; strain; hypertension
2.  Vascular Endothelial Growth Factor Receptor 2 (Vegfr2) Controls Blood Pressure by Regulating Nitric Oxide Synthase Expression 
Hypertension  2009;54(3):652-658.
Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared to vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of ≈10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney (p=0.019) and in urinary excretion of aldosterone (p<0.05). Treatment with the anti-VEGFR2 antibody also caused marked reduction in expression of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) in the kidney. To examine the role of nitric oxide (NO) in the hypertension caused by blocking VEGFR2, mice were treated with Nω-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg/day), an inhibitor of NO production. L-NAME administration abolished the difference in blood pressure between the vehicle- and anti-VEGFR2-treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in blood pressure control by promoting NOS expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by anti-angiogenic agents targeting VEGF.
doi:10.1161/HYPERTENSIONAHA.109.129973
PMCID: PMC2746822  PMID: 19652084
hypertension; angiogenesis; cancer; vascular endothelial growth factor; nitric oxide
3.  Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis 
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 (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A 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 AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B 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 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.
doi:10.1172/JCI34862
PMCID: PMC2662542  PMID: 19287096

Results 1-3 (3)