Cardiovascular characterization of Pkd2+/LacZ mice, an animal model for the autosomal dominant polycystic kidney disease type 2 (ADPKD2)

Stypmann, Jörg; Engelen, Markus A.; Orwat, Stefan; Bilbilis, Konstantinos; Rothenburger, Markus; Eckardt, Lars; Haverkamp, Wilhelm; Horst, Jürgen; Dworniczak, Bernd; Pennekamp, Petra

doi:10.1016/j.ijcard.2006.09.013

Cited by 14 publications

(23 citation statements)

References 47 publications

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“…Tail-cuff measurements of systemic blood pressure revealed no difference in the resting value for conscious 5-mo-old mice (∼130/90 mm Hg for both genotypes; Fig. 5D), consistent with previous studies (21). No pathological differences in Pkd2 +/− were observed in the heart or kidneys (Fig.…”

Section: Resultssupporting

confidence: 91%

“…In WT and Pkd2 +/− mice, all baseline cardiac parameters including left ventricular ejection fraction (LVEF) were within the expected physiological ranges ( Fig. 5B and Table S3), consistent with previously published data (20,21). However, the inner ventricular septum (IVS) and the left ventricular posterior wall (LVPW) were both significantly thinner in the Pkd2 +/− mice compared with WT, but the left ventricular internal diameter (LVID) was unchanged (Fig.…”

Section: Resultssupporting

confidence: 89%

“…Although cardiac studies have been performed in other Pkd2 mouse models, no abnormalities were reported, and thus the Pkd2 mouse is thought to poorly mimic human ADPKD (21). We find here that Pkd2 +/− mice have normal blood pressure and cardiac function.…”

Section: Discussionmentioning

confidence: 60%

“…Studies on heterozygous Pkd2 mice (Pkd2 +/− ) or mice with Pkd1 knocked out in smooth muscle (Pkd1sm −/− ) have not reported cardiac deficits or changes in blood pressure (20)(21)(22), although increased aortic contractility was observed after phenylephrine challenge in Pkd2 +/− mice, and altered vascular pressure sensing responses were observed in Pkd1sm −/− mice (20,22,23). Cardiac developmental defects have been observed in embryonic Pkd2 −/− mice (24), but, as Pkd2 −/− mice die by birth, it is impossible to properly characterize their…”

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confidence: 99%

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Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Kuo¹,

Kwaczala

Nguyen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac disorders are the main cause of mortality in autosomaldominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2 +/− ) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2 +/− cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2 +/− mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2 +/− mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and βAR-2 inhibited the ISO response in Pkd2 +/− mice, suggesting that the dephosphorylated state of PLB is primarily by βAR-2 signaling. Importantly, the Pkd2 +/− mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction.calcium signaling | β-adrenergic receptor blocker | excitation contraction coupling

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

See 2 more Smart Citations

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Kuo¹,

Kwaczala

Nguyen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Heterozygous mutant PKD1 or PKD2 mice appear normal but develop single cysts in the kidney or liver late in life and have a reduced overall lifespan [23, 31]. Homozygous null mutant mice are embryonically lethal and die in utero or perinatally because of systemic defects with massively enlarged cystic kidneys, pancreatic ductal cysts, and pulmonary hypoplasia and often exhibit edema, vascular leaks, and rupture of blood vessels.…”

Section: Definition Classification and Epidemiologymentioning

confidence: 99%

ADPKD: Prototype of Cardiorenal Syndrome Type 4

Virzì

Corradi

Panagiotou

et al. 2011

International Journal of Nephrology

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The cardiorenal syndrome type 4 (Chronic Renocardiac Syndrome) is characterized by a condition of primary chronic kidney disease (CKD) that leads to an impairment of the cardiac function, ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. Clinically, it is very difficult to distinguish between CRS type 2 (Chronic Cardiorenal Syndrome) and CRS type 4 (Chronic Renocardiac Syndrome) because often it is not clear whether the primary cause of the syndrome depends on the heart or the kidney. Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease that causes CKD, could be viewed as an ideal prototype of CRS type 4 because it is certain that the primary cause of cardiorenal syndrome is the kidney disease. In this paper, we will briefly review the epidemiology of ADPKD, conventional and novel biomarkers which may be useful in following the disease process, and prevention and treatment strategies.

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Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation

Singh

Hoogaars

Barnett

et al. 2011

Cell. Mol. Life Sci.

118

135

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A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-011-0884-2) contains supplementary material, which is available to authorized users.

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Cardiovascular characterization of Pkd2+/LacZ mice, an animal model for the autosomal dominant polycystic kidney disease type 2 (ADPKD2)

Cited by 14 publications

References 47 publications

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

ADPKD: Prototype of Cardiorenal Syndrome Type 4

Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation

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