Pkd2+/− Vascular Smooth Muscles Develop Exaggerated Vasocontraction in Response to Phenylephrine Stimulation

Qian, Qi; Hunter, Larry W.; Du, Hui; Ren, Qun; Han, Young Soo; Sieck, Gary C.

doi:10.1681/asn.2006050501

Cited by 55 publications

(53 citation statements)

References 44 publications

(42 reference statements)

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“…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%

“…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: 89%

mentioning

confidence: 99%

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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show abstract

“…Although abnormalities have been reported in Pkd1-and Pkd2-haploinsufficient models, 26,27 the understanding and effects of this condition are still limited. On the basis of the biologic properties of PC1, we reasoned that this condition might lead to increased susceptibility to IR.…”

Section: Discussionmentioning

confidence: 99%

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Bastos

Piontek

Silva

et al. 2009

Journal of the American Society of Nephrology

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Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10-to 12-wk-old male noncystic Pkd1 ϩ/Ϫ and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

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“…7 Immunohistochemical staining for smooth muscle ␣-actin (SMA) was performed as previously described. 19 …”

Section: Cryosections Immunofluorescence and Immunohistochemistrymentioning

confidence: 99%

Characterization of Primary Cilia in Human Airway Smooth Muscle Cells

Wang

et al. 2009

Chest

Self Cite

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Background: Considerable evidence indicates a key role for primary cilia of mammalian cells in mechanochemical sensing. Dysfunctions of primary cilia have been linked to the pathogenesis of several human diseases. However, cilia-related research has been limited to a few cell and tissue types; to our knowledge, no literature exists on primary cilia in airway smooth muscle (ASM). The aim of this study was to characterize primary cilia in human ASM. Methods: Primary cilia of human bronchial smooth muscle cells (HBSMCs) were examined using immunofluorescence confocal microscopy, and scanning and transmission electron microscopy. HBSMC migration and injury repair were examined by scratch-wound and epidermal growth factor (EGF)-induced migration assays.

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Pkd2+/− Vascular Smooth Muscles Develop Exaggerated Vasocontraction in Response to Phenylephrine Stimulation

Cited by 55 publications

References 44 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

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Characterization of Primary Cilia in Human Airway Smooth Muscle Cells

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