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Arora, Pankaj

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Arora

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Pankaj

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Arora, Pankaj
Author's Publications: search.filters.isAuthorOfPublication.73bf4bd4-953b-4b48-9680-d81c47aabb70

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    Atrial natriuretic peptide is negatively regulated by microRNA-425
    (American Society for Clinical Investigation, 2013) Arora, Pankaj; Wu, Connie; Khan, Abigail May; Bloch, Donald; Davis-Dusenbery, Brandi N; Ghorbani, Anahita; Spagnolli, Ester; Martinez, Andrew; Ryan, Allicia; Tainsh, Laurel T.; Kim, Samuel M; Rong, Jian; Huan, Tianxiao; Freedman, Jane E.; Levy, Daniel; Miller, Karen; Hata, Akiko; Del Monte, Federica; Vandenwijngaert, Sara; Swinnen, Melissa; Janssens, Stefan; Holmes, Tara M.; Buys, Emmanuel; Bloch, Kenneth; Newton-Cheh, Christopher; Wang, Thomas Jue-Fuu
    Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
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    Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma
    (Public Library of Science, 2013) Ko, Yu-Chieh; Hayton, Sarah R.; Jones, Alexander; Tainsh, Laurel T.; Ren, Ruiyi; Giani, Andrea; Clerté, Maeva; Abernathy, Emma; de Waard, Nadine; Turcotte, Raphael; Nathan, Daniel; Loomis, Stephanie J.; Gong, Haiyan; Brouckaert, Peter; Buys, Emmanuel; Alt, Clemens; Tainsh, Robert; Oh, Dong-Jin; Malhotra, Rajeev; Arora, Pankaj; Yu, Binglan; Scherrer-Crosbie, Marielle; Kang, Jae Hee; Lin, Charles; Rhee, Douglas J; Wiggs, Janey; Gregory-Ksander, Meredith; Pasquale, Louis; Bloch, Kenneth; Ksander, Bruce
    Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the \(α_1\) subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase \(α_1\)–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the \(α_1\) and \(β_1\) subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.
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    Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension
    (Public Library of Science, 2010) Padmanabhan, Sandosh; Melander, Olle; Johnson, Toby; Di Blasio, Anna Maria; Lee, Wai K.; Gentilini, Davide; Hastie, Claire E.; Menni, Cristina; Monti, Maria Cristina; Delles, Christian; Laing, Stewart; Corso, Barbara; Navis, Gerjan; Kwakernaak, Arjan J.; van der Harst, Pim; Bochud, Murielle; Maillard, Marc; Burnier, Michel; Hedner, Thomas; Kjeldsen, Sverre; Wahlstrand, Björn; Sjögren, Marketa; Fava, Cristiano; Montagnana, Martina; Danese, Elisa; Torffvit, Ole; Hedblad, Bo; Snieder, Harold; Brown, Morris; Samani, Nilesh J.; Farrall, Martin; Cesana, Giancarlo; Mancia, Giuseppe; Signorini, Stefano; Grassi, Guido; Eyheramendy, Susana; Wichmann, H. Erich; Laan, Maris; Strachan, David P.; Sever, Peter; Shields, Denis Colm; Stanton, Alice; Vollenweider, Peter; Teumer, Alexander; Völzke, Henry; Rettig, Rainer; Soranzo, Nicole; Spector, Timothy D.; Lucas, Gavin; Kathiresan, Sekar; Siscovick, David S.; Luan, Jian'an; Loos, Ruth J. F.; Wareham, Nicholas J.; Penninx, Brenda W.; Nolte, Ilja M.; McBride, Martin; Miller, William H.; Nicklin, Stuart A.; Graham, Delyth; Pell, Jill P.; Sattar, Naveed; Welsh, Paul; Munroe, Patricia; Caulfield, Mark J.; Zanchetti, Alberto; Dominiczak, Anna F.; Schork, Nicholas J.; Connell, John M.C.; Newton-Cheh, Christopher; Arora, Pankaj; Feng, Zhang; Baker, Andrew H.; McDonald, Robert A.; Global BPgen Consortium
    Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%–2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84–0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860–0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83–0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83–0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.