Renal cyclooxygenase-2 in obese Zucker (fatty) rats

Radko Komers, Jana Ždychová, Monika Cahová, Ludmila Kazdová, Jessie N. Lindsley, Sharon Anderson

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background. Cyclooxygenase (COX) isoforms, COX-1 and COX-2, are involved in production of prostanoids in the kidney. Increases in renal COX-2 expression have been implicated in the pathophysiology of progressive renal injury, including type 1 diabetes. Thromboxane A2 (TxA2) has been suggested as the key mediator of these effects resulting in up-regulation of prosclerotic cytokines and extracellular matrix proteins. Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes. Methods. Renal cortical COX protein expression, and urinary excretion of stable metabolites of prostaglandin E2 (PGE2) and TxA 2, in association with metabolic parameters, were determined in 4-and 12-week-old Zucker fatty rats (fa/fa rat) (ZDF4 and ZDF12), a model of type 2 diabetes, and in age-matched littermates with no metabolic defect (Zucker lean) (ZL4 and ZL12). Results. Western blotting revealed increased COX-2 expression in ZDF4 as compared to ZL4 (245 ±130% ) (P <0.05). This increase in COX-2 was even more apparent in 12-week-old ZDF rats (650 ±120%) (P <0.01). All groups of rats demonstrated COX-2-positive cells in typical cortical localizations [macula densa, thick ascending loop of Henle (TALH)]. In contrast to COX-2, COX-1 expression was 30% lower in ZDF12. These changes in COX expression were associated with enhanced urinary excretion of prostanoids, in parallel with the development of metabolic abnormalities. Moreover, increases in prostanoid excretion in ZDF12 were in part reduced by wortmannin (100 μg/kg), used as inhibitor of insulin signaling. Conclusion. Renal cortical COX-2 protein expression and function were increased in ZDF rats, as compared to controls, whereas COX-1 exhibited opposite regulation. The changes in COX-2 paralleled metabolic abnormalities, and were at least in part a four consequence of hyperinsulinemia. These abnormalities may play a role in renal pathophysiology in this model of type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)2151-2158
Number of pages8
JournalKidney International
Volume67
Issue number6
DOIs
StatePublished - Jun 2005
Externally publishedYes

Fingerprint

Zucker Rats
Cyclooxygenase 2
Kidney
Prostaglandin-Endoperoxide Synthases
Cyclooxygenase 1
Type 2 Diabetes Mellitus
Prostaglandins
Type 1 Diabetes Mellitus
Loop of Henle
Thromboxane A2
Extracellular Matrix Proteins
Hyperinsulinism
Dinoprostone
Protein Isoforms
Proteins
Up-Regulation
Western Blotting
Insulin
Cytokines
Wounds and Injuries

Keywords

  • Cyclooxygenase-2
  • Diabetic nephropathy
  • Hyperinsulinemia
  • Thromboxane A2
  • Zucker rat

ASJC Scopus subject areas

  • Nephrology

Cite this

Komers, R., Ždychová, J., Cahová, M., Kazdová, L., Lindsley, J. N., & Anderson, S. (2005). Renal cyclooxygenase-2 in obese Zucker (fatty) rats. Kidney International, 67(6), 2151-2158. https://doi.org/10.1111/j.1523-1755.2005.00320.x

Renal cyclooxygenase-2 in obese Zucker (fatty) rats. / Komers, Radko; Ždychová, Jana; Cahová, Monika; Kazdová, Ludmila; Lindsley, Jessie N.; Anderson, Sharon.

In: Kidney International, Vol. 67, No. 6, 06.2005, p. 2151-2158.

Research output: Contribution to journalArticle

Komers, R, Ždychová, J, Cahová, M, Kazdová, L, Lindsley, JN & Anderson, S 2005, 'Renal cyclooxygenase-2 in obese Zucker (fatty) rats', Kidney International, vol. 67, no. 6, pp. 2151-2158. https://doi.org/10.1111/j.1523-1755.2005.00320.x
Komers R, Ždychová J, Cahová M, Kazdová L, Lindsley JN, Anderson S. Renal cyclooxygenase-2 in obese Zucker (fatty) rats. Kidney International. 2005 Jun;67(6):2151-2158. https://doi.org/10.1111/j.1523-1755.2005.00320.x
Komers, Radko ; Ždychová, Jana ; Cahová, Monika ; Kazdová, Ludmila ; Lindsley, Jessie N. ; Anderson, Sharon. / Renal cyclooxygenase-2 in obese Zucker (fatty) rats. In: Kidney International. 2005 ; Vol. 67, No. 6. pp. 2151-2158.
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abstract = "Background. Cyclooxygenase (COX) isoforms, COX-1 and COX-2, are involved in production of prostanoids in the kidney. Increases in renal COX-2 expression have been implicated in the pathophysiology of progressive renal injury, including type 1 diabetes. Thromboxane A2 (TxA2) has been suggested as the key mediator of these effects resulting in up-regulation of prosclerotic cytokines and extracellular matrix proteins. Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes. Methods. Renal cortical COX protein expression, and urinary excretion of stable metabolites of prostaglandin E2 (PGE2) and TxA 2, in association with metabolic parameters, were determined in 4-and 12-week-old Zucker fatty rats (fa/fa rat) (ZDF4 and ZDF12), a model of type 2 diabetes, and in age-matched littermates with no metabolic defect (Zucker lean) (ZL4 and ZL12). Results. Western blotting revealed increased COX-2 expression in ZDF4 as compared to ZL4 (245 ±130{\%} ) (P <0.05). This increase in COX-2 was even more apparent in 12-week-old ZDF rats (650 ±120{\%}) (P <0.01). All groups of rats demonstrated COX-2-positive cells in typical cortical localizations [macula densa, thick ascending loop of Henle (TALH)]. In contrast to COX-2, COX-1 expression was 30{\%} lower in ZDF12. These changes in COX expression were associated with enhanced urinary excretion of prostanoids, in parallel with the development of metabolic abnormalities. Moreover, increases in prostanoid excretion in ZDF12 were in part reduced by wortmannin (100 μg/kg), used as inhibitor of insulin signaling. Conclusion. Renal cortical COX-2 protein expression and function were increased in ZDF rats, as compared to controls, whereas COX-1 exhibited opposite regulation. The changes in COX-2 paralleled metabolic abnormalities, and were at least in part a four consequence of hyperinsulinemia. These abnormalities may play a role in renal pathophysiology in this model of type 2 diabetes.",
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AU - Ždychová, Jana

AU - Cahová, Monika

AU - Kazdová, Ludmila

AU - Lindsley, Jessie N.

AU - Anderson, Sharon

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N2 - Background. Cyclooxygenase (COX) isoforms, COX-1 and COX-2, are involved in production of prostanoids in the kidney. Increases in renal COX-2 expression have been implicated in the pathophysiology of progressive renal injury, including type 1 diabetes. Thromboxane A2 (TxA2) has been suggested as the key mediator of these effects resulting in up-regulation of prosclerotic cytokines and extracellular matrix proteins. Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes. Methods. Renal cortical COX protein expression, and urinary excretion of stable metabolites of prostaglandin E2 (PGE2) and TxA 2, in association with metabolic parameters, were determined in 4-and 12-week-old Zucker fatty rats (fa/fa rat) (ZDF4 and ZDF12), a model of type 2 diabetes, and in age-matched littermates with no metabolic defect (Zucker lean) (ZL4 and ZL12). Results. Western blotting revealed increased COX-2 expression in ZDF4 as compared to ZL4 (245 ±130% ) (P <0.05). This increase in COX-2 was even more apparent in 12-week-old ZDF rats (650 ±120%) (P <0.01). All groups of rats demonstrated COX-2-positive cells in typical cortical localizations [macula densa, thick ascending loop of Henle (TALH)]. In contrast to COX-2, COX-1 expression was 30% lower in ZDF12. These changes in COX expression were associated with enhanced urinary excretion of prostanoids, in parallel with the development of metabolic abnormalities. Moreover, increases in prostanoid excretion in ZDF12 were in part reduced by wortmannin (100 μg/kg), used as inhibitor of insulin signaling. Conclusion. Renal cortical COX-2 protein expression and function were increased in ZDF rats, as compared to controls, whereas COX-1 exhibited opposite regulation. The changes in COX-2 paralleled metabolic abnormalities, and were at least in part a four consequence of hyperinsulinemia. These abnormalities may play a role in renal pathophysiology in this model of type 2 diabetes.

AB - Background. Cyclooxygenase (COX) isoforms, COX-1 and COX-2, are involved in production of prostanoids in the kidney. Increases in renal COX-2 expression have been implicated in the pathophysiology of progressive renal injury, including type 1 diabetes. Thromboxane A2 (TxA2) has been suggested as the key mediator of these effects resulting in up-regulation of prosclerotic cytokines and extracellular matrix proteins. Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes. Methods. Renal cortical COX protein expression, and urinary excretion of stable metabolites of prostaglandin E2 (PGE2) and TxA 2, in association with metabolic parameters, were determined in 4-and 12-week-old Zucker fatty rats (fa/fa rat) (ZDF4 and ZDF12), a model of type 2 diabetes, and in age-matched littermates with no metabolic defect (Zucker lean) (ZL4 and ZL12). Results. Western blotting revealed increased COX-2 expression in ZDF4 as compared to ZL4 (245 ±130% ) (P <0.05). This increase in COX-2 was even more apparent in 12-week-old ZDF rats (650 ±120%) (P <0.01). All groups of rats demonstrated COX-2-positive cells in typical cortical localizations [macula densa, thick ascending loop of Henle (TALH)]. In contrast to COX-2, COX-1 expression was 30% lower in ZDF12. These changes in COX expression were associated with enhanced urinary excretion of prostanoids, in parallel with the development of metabolic abnormalities. Moreover, increases in prostanoid excretion in ZDF12 were in part reduced by wortmannin (100 μg/kg), used as inhibitor of insulin signaling. Conclusion. Renal cortical COX-2 protein expression and function were increased in ZDF rats, as compared to controls, whereas COX-1 exhibited opposite regulation. The changes in COX-2 paralleled metabolic abnormalities, and were at least in part a four consequence of hyperinsulinemia. These abnormalities may play a role in renal pathophysiology in this model of type 2 diabetes.

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KW - Hyperinsulinemia

KW - Thromboxane A2

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