Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells

Adam T. Whaley-Connell, E. Matthew Morris, Nathan Rehmer, J. Cipporah Yaghoubian, Yongzhong Wei, Melvin R. Hayden, Javad Habibi, Craig S Stump, James R. Sowers

Research output: Contribution to journalArticle

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Abstract

Background: Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal tubule cell (PTC). Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria. Methods: To investigate the role of HMG-CoA reductase inhibition of Rac1 and oxidative stress we used the opossum kidney PTC. ROS generation in the PTC was confirmed using oxidative fluorescent dihydroethidium staining. Results: We observed time-dependent increases in NOX activity with bovine serum albumin (albumin) stimulation (500 μg/dl, maximum at 20 min, p < 0.05) that was inhibited in a concentration-dependent manner with the HMG-CoA reductase inhibitor rosuvastatin (1 μM, p < 0.05). Additionally, the Rac1 inhibitor NSC23766 (100 ng/ml) attenuated albumin activation of NOX. Western blot analysis confirmed Rac1 translocation to plasma membrane in the PTC following albumin stimulation and subsequent inhibition by rosuvastatin and NSC23766. Conclusions: These data demonstrate that albumin-mediated increases in NOX activity and ROS in PTC are reversed by inhibition of Rac1 signaling with the use of rosuvastatin.

Original languageEnglish (US)
Pages (from-to)15-23
Number of pages9
JournalAmerican Journal of Nephrology
Volume27
Issue number1
DOIs
StatePublished - Mar 2007

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NADPH Oxidase
Albumins
Reactive Oxygen Species
Hydroxymethylglutaryl CoA Reductases
Albumin Receptors
Oxidative Stress
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Opossums
Proximal Kidney Tubule
Albuminuria
Bovine Serum Albumin
Endocytosis
Guanosine Triphosphate
Western Blotting
Cell Membrane
Staining and Labeling
Rosuvastatin Calcium

Keywords

  • Albumin
  • HMG-CoA reductase inhibitor
  • NAD(P)H oxidase
  • Proximal tubule cell
  • Rac1

ASJC Scopus subject areas

  • Nephrology

Cite this

Whaley-Connell, A. T., Morris, E. M., Rehmer, N., Yaghoubian, J. C., Wei, Y., Hayden, M. R., ... Sowers, J. R. (2007). Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells. American Journal of Nephrology, 27(1), 15-23. https://doi.org/10.1159/000098432

Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells. / Whaley-Connell, Adam T.; Morris, E. Matthew; Rehmer, Nathan; Yaghoubian, J. Cipporah; Wei, Yongzhong; Hayden, Melvin R.; Habibi, Javad; Stump, Craig S; Sowers, James R.

In: American Journal of Nephrology, Vol. 27, No. 1, 03.2007, p. 15-23.

Research output: Contribution to journalArticle

Whaley-Connell, AT, Morris, EM, Rehmer, N, Yaghoubian, JC, Wei, Y, Hayden, MR, Habibi, J, Stump, CS & Sowers, JR 2007, 'Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells', American Journal of Nephrology, vol. 27, no. 1, pp. 15-23. https://doi.org/10.1159/000098432
Whaley-Connell AT, Morris EM, Rehmer N, Yaghoubian JC, Wei Y, Hayden MR et al. Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells. American Journal of Nephrology. 2007 Mar;27(1):15-23. https://doi.org/10.1159/000098432
Whaley-Connell, Adam T. ; Morris, E. Matthew ; Rehmer, Nathan ; Yaghoubian, J. Cipporah ; Wei, Yongzhong ; Hayden, Melvin R. ; Habibi, Javad ; Stump, Craig S ; Sowers, James R. / Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells. In: American Journal of Nephrology. 2007 ; Vol. 27, No. 1. pp. 15-23.
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AU - Morris, E. Matthew

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AU - Wei, Yongzhong

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N2 - Background: Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal tubule cell (PTC). Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria. Methods: To investigate the role of HMG-CoA reductase inhibition of Rac1 and oxidative stress we used the opossum kidney PTC. ROS generation in the PTC was confirmed using oxidative fluorescent dihydroethidium staining. Results: We observed time-dependent increases in NOX activity with bovine serum albumin (albumin) stimulation (500 μg/dl, maximum at 20 min, p < 0.05) that was inhibited in a concentration-dependent manner with the HMG-CoA reductase inhibitor rosuvastatin (1 μM, p < 0.05). Additionally, the Rac1 inhibitor NSC23766 (100 ng/ml) attenuated albumin activation of NOX. Western blot analysis confirmed Rac1 translocation to plasma membrane in the PTC following albumin stimulation and subsequent inhibition by rosuvastatin and NSC23766. Conclusions: These data demonstrate that albumin-mediated increases in NOX activity and ROS in PTC are reversed by inhibition of Rac1 signaling with the use of rosuvastatin.

AB - Background: Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal tubule cell (PTC). Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria. Methods: To investigate the role of HMG-CoA reductase inhibition of Rac1 and oxidative stress we used the opossum kidney PTC. ROS generation in the PTC was confirmed using oxidative fluorescent dihydroethidium staining. Results: We observed time-dependent increases in NOX activity with bovine serum albumin (albumin) stimulation (500 μg/dl, maximum at 20 min, p < 0.05) that was inhibited in a concentration-dependent manner with the HMG-CoA reductase inhibitor rosuvastatin (1 μM, p < 0.05). Additionally, the Rac1 inhibitor NSC23766 (100 ng/ml) attenuated albumin activation of NOX. Western blot analysis confirmed Rac1 translocation to plasma membrane in the PTC following albumin stimulation and subsequent inhibition by rosuvastatin and NSC23766. Conclusions: These data demonstrate that albumin-mediated increases in NOX activity and ROS in PTC are reversed by inhibition of Rac1 signaling with the use of rosuvastatin.

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