Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats

Abstract

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500mg/kg, ip), an inhibitor of LTA(4) synthesis, 1h before NDPS (0.4mmol/kg, ip), N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4mmol/kg, ip), or N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD(4) receptor antagonist LY171883 (100mg/kg, po) was administered 0.5h before and again 6h after NDHS (0.1mmol/kg, ip) or 2-NDHSA (0.1mmol/kg, ip) or vehicle. Renal function was monitored for 48h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity.

Figure 1

Pathway production of prostaglandins, thromboxanes and leukotrienes from arachidonic acid and sites of potential inhibitors. BSO = buthionine sulfoximine; DAZ = dazmegrel; DEC = diethylcarbamazine; DEM = diethyl maleate; 5-(S)-HPETE = 5-(S)-hydroperoxyeicosatetraenoic acid; INDO = indomethacin; 5-LOX = 5-lipoxygenase; LTA₄ (C₄, D₄, E₄) = leukotriene A₄ (C₄, D₄, E₄); PGH₂ (E₂; I₂) = prostaglandin H₂ (E₂; I₂); PHS = prostaglandin H synthase; TxA₂ = thromboxane A₂.

Figure 2

The effect of DEC pretreatment on NDPS-induced changes in BUN concentration. Rats (4 per group) were administered DEC (250 mg/kg, ip) 1 h before an ip injection of NDPS (0.4 mmol/kg) (treated) or the appropriate vehicle (control). Blood samples were obtained at 48 post-treatment following NDPS or vehicle administration. Values are means ± S.E. A diamond indicates significantly different from the appropriate control group value for that day’s measurement, p < 0.05. An asterisk indicates significantly different from the corresponding day 0 value, p < 0.05. A gamma indicates significantly different from the NDPS only value for the day 2 measurement, p < 0.05.

Figure 3

The effect of DEC pretreatment on NDPS metabolite-induced changes in BUN concentration. Rats (4 per group) were administered DEC (250 mg/kg, ip) 1 h before an ip injection of NDHS (0.1 mmol/kg)(A) or 2-NDHSA (0.1 mmol/kg)(B) (treated) or the appropriate vehicle (control). Blood samples were obtained at 48 post-treatment following the NDPS metabolite or vehicle administration. Values are means ± S.E. A diamond indicates significantly different from the appropriate control group value for that day’s measurement, p < 0.05. An asterisk indicates significantly different from the corresponding day 0 value, p < 0.05. A gamma indicates significantly different from the NDPS metabolite only value for the day 2 measurement, p < 0.05.

Figure 3

The effect of DEC pretreatment on NDPS metabolite-induced changes in BUN concentration. Rats (4 per group) were administered DEC (250 mg/kg, ip) 1 h before an ip injection of NDHS (0.1 mmol/kg)(A) or 2-NDHSA (0.1 mmol/kg)(B) (treated) or the appropriate vehicle (control). Blood samples were obtained at 48 post-treatment following the NDPS metabolite or vehicle administration. Values are means ± S.E. A diamond indicates significantly different from the appropriate control group value for that day’s measurement, p < 0.05. An asterisk indicates significantly different from the corresponding day 0 value, p < 0.05. A gamma indicates significantly different from the NDPS metabolite only value for the day 2 measurement, p < 0.05.

Figure 4

The effect of DEC pretreatment on 2-NDHSA-induced changes on proximal tubule morphology at 48 hr post 2-NDHSA treatment. Panel A shows renal cortex from a rat administered 2-NDHSA vehicle (control); panel B shows renal cortex from a rat administered DEC (250mg/kg); panel C shows renal cortex from a rat administered 2-NDHSA (0.1 mmol/kg), note the marked proximal tubular necrosis; and panel D shows renal cortex from a rat administered DEC (250 mg/kg) prior to 2-NDHSA (0.1 mmol/kg). Magnification was x200.