Urea-induced ROS cause endothelial dysfunction in chronic renal failure

Maria D'Apolito, Xue-Liang Du, Daniela Pisanelli, Massimo Pettoello-Mantovani, Angelo Campanozzi, Ferdinando Giacco, Angela Bruna Maffione, Anna Laura Colia, Michael Brownlee, Ida Giardino

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Objective: The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia. Methods: Primary cultures of human aortic endothelial cells (HAEC) were exposed to 20. mM urea for 48h. C57BL/6J wild-type mice underwent 5/6 nephrectomy or a sham operation. Randomized groups of 5/6 nephrectomized mice and their controls were also injected i.p. with a SOD/catalase mimetic (MnTBAP) for 15 days starting immediately after the final surgical procedure. Results: Urea at concentrations seen in CRF induced mitochondrial ROS production in cultured HAEC. Urea-induced ROS caused the activation of endothelial pro-inflammatory pathways through the inhibition of GAPDH, including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular AGEs (advanced glycation end products). Urea-induced ROS directly inactivated the anti-atherosclerosis enzyme PGI2 synthase and also caused ER stress. Normalization of mitochondrial ROS production prevented each of these effects of urea. In uremic mice, treatment with MnTBAP prevented aortic oxidative stress, PGI2 synthase activity reduction and increased expression of the pro-inflammatory proteins TNFα, IL-6, VCAM1, Endoglin, and MCP-1. Conclusions: Taken together, these data show that urea itself, at levels common in patients with CRF, causes endothelial dysfunction and activation of proatherogenic pathways.

Original languageEnglish (US)
Pages (from-to)393-400
Number of pages8
JournalAtherosclerosis
Volume239
Issue number2
DOIs
StatePublished - Apr 1 2015

Fingerprint

Chronic Kidney Failure
Urea
Endothelial Cells
Atherosclerosis
Hexosamines
Advanced Glycosylation End Products
Nephrectomy
Adipocytes
Hyperglycemia
Catalase
Protein Kinase C
Interleukin-6
Protein Isoforms
Oxidative Stress
Enzymes
Proteins

Keywords

  • Chronic renal failure
  • CRF
  • Endothelial cells
  • GlcNAc
  • Manganese tetrakis (4-benzoic acid) porphyrin
  • MnTBAP
  • O-linked-N-acetylglucosamine
  • Prostacyclin synthase
  • Reactive oxygen species
  • ROS
  • ROS
  • UCP-1
  • Uncoupling protein 1
  • Urea

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

D'Apolito, M., Du, X-L., Pisanelli, D., Pettoello-Mantovani, M., Campanozzi, A., Giacco, F., ... Giardino, I. (2015). Urea-induced ROS cause endothelial dysfunction in chronic renal failure. Atherosclerosis, 239(2), 393-400. https://doi.org/10.1016/j.atherosclerosis.2015.01.034

Urea-induced ROS cause endothelial dysfunction in chronic renal failure. / D'Apolito, Maria; Du, Xue-Liang; Pisanelli, Daniela; Pettoello-Mantovani, Massimo; Campanozzi, Angelo; Giacco, Ferdinando; Maffione, Angela Bruna; Colia, Anna Laura; Brownlee, Michael; Giardino, Ida.

In: Atherosclerosis, Vol. 239, No. 2, 01.04.2015, p. 393-400.

Research output: Contribution to journalArticle

D'Apolito, M, Du, X-L, Pisanelli, D, Pettoello-Mantovani, M, Campanozzi, A, Giacco, F, Maffione, AB, Colia, AL, Brownlee, M & Giardino, I 2015, 'Urea-induced ROS cause endothelial dysfunction in chronic renal failure', Atherosclerosis, vol. 239, no. 2, pp. 393-400. https://doi.org/10.1016/j.atherosclerosis.2015.01.034
D'Apolito M, Du X-L, Pisanelli D, Pettoello-Mantovani M, Campanozzi A, Giacco F et al. Urea-induced ROS cause endothelial dysfunction in chronic renal failure. Atherosclerosis. 2015 Apr 1;239(2):393-400. https://doi.org/10.1016/j.atherosclerosis.2015.01.034
D'Apolito, Maria ; Du, Xue-Liang ; Pisanelli, Daniela ; Pettoello-Mantovani, Massimo ; Campanozzi, Angelo ; Giacco, Ferdinando ; Maffione, Angela Bruna ; Colia, Anna Laura ; Brownlee, Michael ; Giardino, Ida. / Urea-induced ROS cause endothelial dysfunction in chronic renal failure. In: Atherosclerosis. 2015 ; Vol. 239, No. 2. pp. 393-400.
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abstract = "Objective: The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia. Methods: Primary cultures of human aortic endothelial cells (HAEC) were exposed to 20. mM urea for 48h. C57BL/6J wild-type mice underwent 5/6 nephrectomy or a sham operation. Randomized groups of 5/6 nephrectomized mice and their controls were also injected i.p. with a SOD/catalase mimetic (MnTBAP) for 15 days starting immediately after the final surgical procedure. Results: Urea at concentrations seen in CRF induced mitochondrial ROS production in cultured HAEC. Urea-induced ROS caused the activation of endothelial pro-inflammatory pathways through the inhibition of GAPDH, including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular AGEs (advanced glycation end products). Urea-induced ROS directly inactivated the anti-atherosclerosis enzyme PGI2 synthase and also caused ER stress. Normalization of mitochondrial ROS production prevented each of these effects of urea. In uremic mice, treatment with MnTBAP prevented aortic oxidative stress, PGI2 synthase activity reduction and increased expression of the pro-inflammatory proteins TNFα, IL-6, VCAM1, Endoglin, and MCP-1. Conclusions: Taken together, these data show that urea itself, at levels common in patients with CRF, causes endothelial dysfunction and activation of proatherogenic pathways.",
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AU - D'Apolito, Maria

AU - Du, Xue-Liang

AU - Pisanelli, Daniela

AU - Pettoello-Mantovani, Massimo

AU - Campanozzi, Angelo

AU - Giacco, Ferdinando

AU - Maffione, Angela Bruna

AU - Colia, Anna Laura

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AB - Objective: The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia. Methods: Primary cultures of human aortic endothelial cells (HAEC) were exposed to 20. mM urea for 48h. C57BL/6J wild-type mice underwent 5/6 nephrectomy or a sham operation. Randomized groups of 5/6 nephrectomized mice and their controls were also injected i.p. with a SOD/catalase mimetic (MnTBAP) for 15 days starting immediately after the final surgical procedure. Results: Urea at concentrations seen in CRF induced mitochondrial ROS production in cultured HAEC. Urea-induced ROS caused the activation of endothelial pro-inflammatory pathways through the inhibition of GAPDH, including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular AGEs (advanced glycation end products). Urea-induced ROS directly inactivated the anti-atherosclerosis enzyme PGI2 synthase and also caused ER stress. Normalization of mitochondrial ROS production prevented each of these effects of urea. In uremic mice, treatment with MnTBAP prevented aortic oxidative stress, PGI2 synthase activity reduction and increased expression of the pro-inflammatory proteins TNFα, IL-6, VCAM1, Endoglin, and MCP-1. Conclusions: Taken together, these data show that urea itself, at levels common in patients with CRF, causes endothelial dysfunction and activation of proatherogenic pathways.

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KW - Prostacyclin synthase

KW - Reactive oxygen species

KW - ROS

KW - ROS

KW - UCP-1

KW - Uncoupling protein 1

KW - Urea

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