Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease

Carla Zoja, Daniela Corna, Giuditta Benedetti, Marina Morigi, Roberta Donadelli, Angelo Guglielmotti, Mario Pinza, Tullio Bertani, Giuseppe Remuzzi

Research output: Contribution to journalArticlepeer-review

Abstract

Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease. As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-{[1- phenylmethyl)-1H-indazol-3-y1]methoxy}propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P <0.005; 10 months: 53% vs. 80%) and significantly (P <0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 ± 3 vs. 127 ± 42; 10 months, 53 ± 5 vs. 140 ± 37 mg/dl). Appearance of anti- DNA antibodies was retarded and survival significantly (P <0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7- 12-fold in 8- 10-month-old mice vs. 2-month- old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies proteinuria and survival of lupus mice, in an additional group of animals (N = 16). Thus, at 14.5 months when all mice given bindarit alone died, 50% of mice on combined therapy were still alive (P <0.023). Studies are needed to establish whether bindarit may function as asteroid sparing drug in human lupus.

Original languageEnglish
Pages (from-to)726-734
Number of pages9
JournalKidney International
Volume53
Issue number3
DOIs
Publication statusPublished - 1998

Keywords

  • Glomerular hypercellularity
  • Immunosuppression
  • Inflammation
  • Lupus nephritis
  • Monocyte chemoattractant protein-1
  • Murine lupus autoimmune disease

ASJC Scopus subject areas

  • Nephrology

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