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

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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
Issue number3
Publication statusPublished - 1998


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

ASJC Scopus subject areas

  • Nephrology


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