Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model

Stacey Dineen Rodenbeck, Chad A. Zarse, Mikaela L. McKenney-Drake, Rebecca S. Bruning, Michael Sturek, Xuening (Neal) Chen, Sharon Moe

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Vascular smooth muscle cells (VSMCs) exhibit phenotypic plasticity, promoting vascular calcification and increasing cardiovascular risk. Changes in VSMC intracellular calcium ([Ca2+]i) are a major determinant of plasticity, but little is known about changes in [Ca2+]i in chronic kidney disease (CKD). We have previously demonstrated such plasticity in aortas from our rat model of CKD and therefore sought to examine changes in [Ca2+]i during CKD progression. Materials and Methods: We examined freshly isolated VSMCs from aortas of normal rats, Cy/+ rats (CKD) with early and advanced CKD, and advanced CKD rats treated without and with 3% calcium gluconate (CKD + Ca2+) to lower parathyroid hormone (PTH) levels. [Ca2+]i was measured with fura-2. Results: Cy/+ rats developed progressive CKD, as assessed by plasma levels of blood urea nitrogen, calcium, phosphorus, parathyroid hormone and fibroblast growth factor 23. VSMCs isolated from rats with CKD demonstrated biphasic alterations in resting [Ca2+]i: VSMCs from rats with early CKD exhibited reduced resting [Ca2+]i, while VSMCs from rats with advanced CKD exhibited elevated resting [Ca2+]i. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ store release was modestly increased in early CKD and was more drastically increased in advanced CKD. The advanced CKD elevation in SR Ca2+ store release was associated with a significant increase in the activity of the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA); however, SERCA2a protein expression was decreased in advanced CKD. Following SR Ca2+ store release, recovery of [Ca2+]i in the presence of caffeine and extracellular Ca2+ was attenuated in VSMCs from rats with advanced CKD. This impairment, together with reductions in expression of the Na+/Ca2+ exchanger, suggest a reduction in Ca2+ extrusion capability. Finally, store-operated Ca2+ entry (SOCE) was assessed following SR Ca2+ store depletion. Ca2+ entry during recovery from caffeine-induced SR Ca2+ store release was elevated in advanced CKD, suggesting a role for exacerbated SOCE with progressing CKD. Conclusions: With progressive CKD in the Cy/+ rat there is increased resting [Ca2+]i in VSMCs due, in part, to increased SOCE and impaired calcium extrusion from the cell. Such changes may predispose VSMCs to phenotypic changes that are a prerequisite to calcification.

Original languageEnglish (US)
Pages (from-to)450-458
Number of pages9
JournalNephrology Dialysis Transplantation
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2017

Fingerprint

Chronic Renal Insufficiency
Vascular Smooth Muscle
Smooth Muscle Myocytes
Calcium
Sarcoplasmic Reticulum
Caffeine
Parathyroid Hormone
Aorta
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Calcium Gluconate
Vascular Calcification
Fura-2
Blood Urea Nitrogen

Keywords

  • calcium signaling
  • cell phenotype
  • chronic kidney disease
  • rat model
  • vascular smooth muscle cells

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model. / Rodenbeck, Stacey Dineen; Zarse, Chad A.; McKenney-Drake, Mikaela L.; Bruning, Rebecca S.; Sturek, Michael; Chen, Xuening (Neal); Moe, Sharon.

In: Nephrology Dialysis Transplantation, Vol. 32, No. 3, 01.03.2017, p. 450-458.

Research output: Contribution to journalArticle

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abstract = "Background: Vascular smooth muscle cells (VSMCs) exhibit phenotypic plasticity, promoting vascular calcification and increasing cardiovascular risk. Changes in VSMC intracellular calcium ([Ca2+]i) are a major determinant of plasticity, but little is known about changes in [Ca2+]i in chronic kidney disease (CKD). We have previously demonstrated such plasticity in aortas from our rat model of CKD and therefore sought to examine changes in [Ca2+]i during CKD progression. Materials and Methods: We examined freshly isolated VSMCs from aortas of normal rats, Cy/+ rats (CKD) with early and advanced CKD, and advanced CKD rats treated without and with 3{\%} calcium gluconate (CKD + Ca2+) to lower parathyroid hormone (PTH) levels. [Ca2+]i was measured with fura-2. Results: Cy/+ rats developed progressive CKD, as assessed by plasma levels of blood urea nitrogen, calcium, phosphorus, parathyroid hormone and fibroblast growth factor 23. VSMCs isolated from rats with CKD demonstrated biphasic alterations in resting [Ca2+]i: VSMCs from rats with early CKD exhibited reduced resting [Ca2+]i, while VSMCs from rats with advanced CKD exhibited elevated resting [Ca2+]i. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ store release was modestly increased in early CKD and was more drastically increased in advanced CKD. The advanced CKD elevation in SR Ca2+ store release was associated with a significant increase in the activity of the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA); however, SERCA2a protein expression was decreased in advanced CKD. Following SR Ca2+ store release, recovery of [Ca2+]i in the presence of caffeine and extracellular Ca2+ was attenuated in VSMCs from rats with advanced CKD. This impairment, together with reductions in expression of the Na+/Ca2+ exchanger, suggest a reduction in Ca2+ extrusion capability. Finally, store-operated Ca2+ entry (SOCE) was assessed following SR Ca2+ store depletion. Ca2+ entry during recovery from caffeine-induced SR Ca2+ store release was elevated in advanced CKD, suggesting a role for exacerbated SOCE with progressing CKD. Conclusions: With progressive CKD in the Cy/+ rat there is increased resting [Ca2+]i in VSMCs due, in part, to increased SOCE and impaired calcium extrusion from the cell. Such changes may predispose VSMCs to phenotypic changes that are a prerequisite to calcification.",
keywords = "calcium signaling, cell phenotype, chronic kidney disease, rat model, vascular smooth muscle cells",
author = "Rodenbeck, {Stacey Dineen} and Zarse, {Chad A.} and McKenney-Drake, {Mikaela L.} and Bruning, {Rebecca S.} and Michael Sturek and Chen, {Xuening (Neal)} and Sharon Moe",
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T1 - Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model

AU - Rodenbeck, Stacey Dineen

AU - Zarse, Chad A.

AU - McKenney-Drake, Mikaela L.

AU - Bruning, Rebecca S.

AU - Sturek, Michael

AU - Chen, Xuening (Neal)

AU - Moe, Sharon

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N2 - Background: Vascular smooth muscle cells (VSMCs) exhibit phenotypic plasticity, promoting vascular calcification and increasing cardiovascular risk. Changes in VSMC intracellular calcium ([Ca2+]i) are a major determinant of plasticity, but little is known about changes in [Ca2+]i in chronic kidney disease (CKD). We have previously demonstrated such plasticity in aortas from our rat model of CKD and therefore sought to examine changes in [Ca2+]i during CKD progression. Materials and Methods: We examined freshly isolated VSMCs from aortas of normal rats, Cy/+ rats (CKD) with early and advanced CKD, and advanced CKD rats treated without and with 3% calcium gluconate (CKD + Ca2+) to lower parathyroid hormone (PTH) levels. [Ca2+]i was measured with fura-2. Results: Cy/+ rats developed progressive CKD, as assessed by plasma levels of blood urea nitrogen, calcium, phosphorus, parathyroid hormone and fibroblast growth factor 23. VSMCs isolated from rats with CKD demonstrated biphasic alterations in resting [Ca2+]i: VSMCs from rats with early CKD exhibited reduced resting [Ca2+]i, while VSMCs from rats with advanced CKD exhibited elevated resting [Ca2+]i. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ store release was modestly increased in early CKD and was more drastically increased in advanced CKD. The advanced CKD elevation in SR Ca2+ store release was associated with a significant increase in the activity of the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA); however, SERCA2a protein expression was decreased in advanced CKD. Following SR Ca2+ store release, recovery of [Ca2+]i in the presence of caffeine and extracellular Ca2+ was attenuated in VSMCs from rats with advanced CKD. This impairment, together with reductions in expression of the Na+/Ca2+ exchanger, suggest a reduction in Ca2+ extrusion capability. Finally, store-operated Ca2+ entry (SOCE) was assessed following SR Ca2+ store depletion. Ca2+ entry during recovery from caffeine-induced SR Ca2+ store release was elevated in advanced CKD, suggesting a role for exacerbated SOCE with progressing CKD. Conclusions: With progressive CKD in the Cy/+ rat there is increased resting [Ca2+]i in VSMCs due, in part, to increased SOCE and impaired calcium extrusion from the cell. Such changes may predispose VSMCs to phenotypic changes that are a prerequisite to calcification.

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KW - cell phenotype

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