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Browsing by Author "Kowala, Mark C."
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Item Author Correction: Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice(Springer Nature, 2018-10-25) Gu, Huiying; Ma, Zhizhong; Wang, Jian; Zhu, Timothy; Du, Nicole; Shatara, Adam; Yi, Xin; Kowala, Mark C.; Du, Yansheng; Neurology, School of MedicineA correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.Item Distinct hemodynamic responses to (pyr)apelin-13 in large animal models(APS, 2020-04) Tune, Johnathan D.; Baker, Hana E.; Berwick, Zachary; Moberly, Steven P.; Casalini, Eli D.; Noblet, Jillian N.; Zhen, Eugene; Kowala, Mark C.; Christe, Michael E.; Goodwill, Adam; Cellular and Integrative Physiology, School of MedicineThis study tested the hypothesis that (pyr)apelin-13 dose-dependently augments myocardial contractility and coronary blood flow, irrespective of changes in systemic hemodynamics. Acute effects of intravenous (pyr)apelin-13 administration (10 to 1,000 nM) on blood pressure, heart rate, left ventricular pressure and volume, and coronary parameters were measured in dogs and pigs. Administration of (pyr)apelin-13 did not influence blood pressure (P = 0.59), dP/dtmax (P = 0.26), or dP/dtmin (P = 0.85) in dogs. However, heart rate dose-dependently increased > 70% (P < 0.01), which was accompanied by a significant increase in coronary blood flow (P < 0.05) and reductions in left ventricular end-diastolic volume and stroke volume (P < 0.001). In contrast, (pyr)apelin-13 did not significantly affect hemodynamics, coronary blood flow, or indexes of contractile function in pigs. Furthermore, swine studies found no effect of intracoronary (pyr)apelin-13 administration on coronary blood flow (P = 0.83) or vasorelaxation in isolated, endothelium-intact (P = 0.89) or denuded (P = 0.38) coronary artery rings. Examination of all data across (pyr)apelin-13 concentrations revealed an exponential increase in cardiac output as peripheral resistance decreased across pigs and dogs (P < 0.001; R2 = 0.78). Assessment of the Frank-Starling relationship demonstrated a significant linear relationship between left ventricular end-diastolic volume and stroke volume across species (P < 0.001; R2 = 0.70). Taken together, these findings demonstrate that (pyr)apelin-13 does not directly influence myocardial contractility or coronary blood flow in either dogs or pigs.Item Phosphodiesterase 1 (PDE1) at the crossroads of calcium and cyclic nucleotide signaling in diabetic nephropathy(2020-05) Dey, Asim Bikash; Aguilar, Ruben C.; Dai, Guoli; Atkinson, Simon J.; Kowala, Mark C.; Baucum II, Anthony J.Diabetic Kidney Disease (DKD) is a major complication of diabetes. Incomplete understanding of its molecular mechanisms is highlighted by the limited treatments options. We hypothesized that inhibition of protective endogenous mechanisms plays major role in the pathogenesis of DKD. While renoprotection is mediated by cyclic nucleotides (cAMP and cGMP), phosphodiesterases (PDEs) lead to cyclic nucleotide degradation. Our investigation focused on the role of calcium/calmodulin activated PDE1 in DKD. Three isoforms of PDE1 are differentially expressed in vascular smooth muscle cells, renal tubular epithelial cells, podocytes, and mesangial cells. We used highly potent and selective PDE1 inhibitor LY1 to explore systemic hemodynamic and local renal role of PDE1. LY1 reduced systolic and diastolic blood pressure in normotensive and spontaneously hypertensive rats. Renal protection with PDE1 inhibition was tested in mouse model of DKD, featuring a combination of diabetes, nephron loss and arterial hypertension. In this model, a PDE1 inhibitor caused a significant improvement in renal function as evident by significant reduction of albuminuria, serum creatinine and several urine biomarkers of inflammation and injury. Histopathological analysis revealed substantial improvement in the pathology of DKD in the treated group that was associated with the reduction of gene expression related to inflammation and fibrosis. Thus, we revealed the role of calcium activated PDE1 in DKD. However, the source of calcium in this context remained obscure. Our bioinformatics analysis pointed out that calcium channel TRPC6 is likely to be involved. Further in vitro studies demonstrated that TRPC6 activation induced apoptosis in human mesangial cells and isolated rat glomeruli, which was attenuated by both TRPC6 and PDE1 inhibition, thereby suggesting a functional coupling between TRPC6 (as a source of calcium) and PDE1 activation. Moving upstream, we showed that several systemic risk factors of DKD (angiotensin II, endothelin 1 and glucose) activated TRPC6 in a different manner, through generation of either reactive oxygen species or diacylglycerol. The computational modeling to relate human transcriptomic and phenotype data demonstrated the pre-clinical findings of renal benefit upon PDE1 inhibition is translatable in human. Taken together, our results suggest mechanistic link among systemic risk factors, TRPC6, calcium flux and PDE1 activation in pathogenesis of DKD. As a corollary, PDE1 inhibition leads to direct and indirect renoprotective effects.Item Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice(Springer Nature, 2017-03-28) Gu, Huiying; Ma, Zhizhong; Wang, Jian; Zhu, Timothy; Du, Nicole; Shatara, Adam; Yi, Xin; Kowala, Mark C.; Du, Yansheng; Department of Neurology, IU School of MedicineHypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/− mice. On high salt diet (HS), BPs of hAS+/− mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/− mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.