Thromboxane receptor blockade reduces renal injury in murine lupus nephritis

Robert F. Spurney, Pang Yen Fan, Phillip Ruiz, Fred Sanfilippo, David S. Pisetsky, Thomas M. Coffman

Research output: Contribution to journalArticle

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Abstract

To investigate the role of thromboxane A2 (TxA2) in murine lupus, we assessed the effects of the specific thromboxane receptor antagonist GR32191 on immune complex glomerulonephritis in MRL-lpr/lpr mice. Forty mg/kg/day GR32191 was given by twice daily subcutaneous injection for eight weeks beginning at 12 weeks of age. This dose completely blocked the renal vasoconstriction produced by the thromboxane agonist U46619. After eight weeks of treatment, both glomerular filtration rate (GFR) (8.9 ± 0.6 vs. 6.8 ± 1.1 ml/min/kg; P <0.05) and PAH clearance (CPAH) (37.4 ± 2.5 vs. 29.9 ± 3.3 ml/min/kg; P<0.05) were significantly higher in mice given GR32191 compared to vehicle treated animals. Administration of GR32191 also reduced proteinuria from 18.1 ± 11.6 to 3.7 ± 1.3 mg/24 hours (P <0.05). In GR32191 treated MRL-lpr/lpr mice, renal hemodynamic function and proteinuria were not significantly different from congenic MRL-+/+ controls. Thromboxane receptor blockade had striking affects on renal histomorphology reducing both hyaline thrombi in glomeruli (P = 0.022) and interstitial inflammation (P = 0.006). Glomerular crescents and severity of vasculitis also tended to be reduced in mice receiving the thromboxane receptor antagonist. The overall histopathologic score in mice given GR32191 was significantly lower than vehicle treated animals (4.7 ± 0.5 vs. 8.4 ± 1.5; P = 0.016). These effects of GR32191 were associated with decreased excretion of thromboxane B2 (TxB2) in urine (292 ± 37 vs. 747 ± 155 pg/24 hr; P <0.005) as well as a modest reduction in glomerular deposits of IgG (semiquantitative score 2.6 ± 0.2 vs. 3.5 ± 0.2; P <0.02). Thus, chronic thromboxane receptor blockade markedly altered the course of renal disease in MRL-lpr/lpr mice, suggesting that TxA2 is an important mediator of renal dysfunction and injury in this murine model of lupus nephritis.

Original languageEnglish
Pages (from-to)973-982
Number of pages10
JournalKidney International
Volume41
Issue number4
StatePublished - Apr 1 1992
Externally publishedYes

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Thromboxane Receptors
Lupus Nephritis
Kidney
Wounds and Injuries
Thromboxane A2
Proteinuria
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Thromboxane B2
Hyalin
Thromboxanes
Subcutaneous Injections
Glomerulonephritis
Vasculitis
vapiprost
Antigen-Antibody Complex
Vasoconstriction
Glomerular Filtration Rate
Thrombosis
Immunoglobulin G
Hemodynamics

ASJC Scopus subject areas

  • Nephrology

Cite this

Spurney, R. F., Fan, P. Y., Ruiz, P., Sanfilippo, F., Pisetsky, D. S., & Coffman, T. M. (1992). Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. Kidney International, 41(4), 973-982.

Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. / Spurney, Robert F.; Fan, Pang Yen; Ruiz, Phillip; Sanfilippo, Fred; Pisetsky, David S.; Coffman, Thomas M.

In: Kidney International, Vol. 41, No. 4, 01.04.1992, p. 973-982.

Research output: Contribution to journalArticle

Spurney, RF, Fan, PY, Ruiz, P, Sanfilippo, F, Pisetsky, DS & Coffman, TM 1992, 'Thromboxane receptor blockade reduces renal injury in murine lupus nephritis', Kidney International, vol. 41, no. 4, pp. 973-982.
Spurney RF, Fan PY, Ruiz P, Sanfilippo F, Pisetsky DS, Coffman TM. Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. Kidney International. 1992 Apr 1;41(4):973-982.
Spurney, Robert F. ; Fan, Pang Yen ; Ruiz, Phillip ; Sanfilippo, Fred ; Pisetsky, David S. ; Coffman, Thomas M. / Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. In: Kidney International. 1992 ; Vol. 41, No. 4. pp. 973-982.
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abstract = "To investigate the role of thromboxane A2 (TxA2) in murine lupus, we assessed the effects of the specific thromboxane receptor antagonist GR32191 on immune complex glomerulonephritis in MRL-lpr/lpr mice. Forty mg/kg/day GR32191 was given by twice daily subcutaneous injection for eight weeks beginning at 12 weeks of age. This dose completely blocked the renal vasoconstriction produced by the thromboxane agonist U46619. After eight weeks of treatment, both glomerular filtration rate (GFR) (8.9 ± 0.6 vs. 6.8 ± 1.1 ml/min/kg; P <0.05) and PAH clearance (CPAH) (37.4 ± 2.5 vs. 29.9 ± 3.3 ml/min/kg; P<0.05) were significantly higher in mice given GR32191 compared to vehicle treated animals. Administration of GR32191 also reduced proteinuria from 18.1 ± 11.6 to 3.7 ± 1.3 mg/24 hours (P <0.05). In GR32191 treated MRL-lpr/lpr mice, renal hemodynamic function and proteinuria were not significantly different from congenic MRL-+/+ controls. Thromboxane receptor blockade had striking affects on renal histomorphology reducing both hyaline thrombi in glomeruli (P = 0.022) and interstitial inflammation (P = 0.006). Glomerular crescents and severity of vasculitis also tended to be reduced in mice receiving the thromboxane receptor antagonist. The overall histopathologic score in mice given GR32191 was significantly lower than vehicle treated animals (4.7 ± 0.5 vs. 8.4 ± 1.5; P = 0.016). These effects of GR32191 were associated with decreased excretion of thromboxane B2 (TxB2) in urine (292 ± 37 vs. 747 ± 155 pg/24 hr; P <0.005) as well as a modest reduction in glomerular deposits of IgG (semiquantitative score 2.6 ± 0.2 vs. 3.5 ± 0.2; P <0.02). Thus, chronic thromboxane receptor blockade markedly altered the course of renal disease in MRL-lpr/lpr mice, suggesting that TxA2 is an important mediator of renal dysfunction and injury in this murine model of lupus nephritis.",
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