Acute nephrotoxicity of aristolochic acids in mice

Abstract

Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.

Selective Toxicity of Aristolochic Acids I and II

“…Our results are generally consistent with those of an earlier study using several strains of mice in which AA-I and AA-II were administered i.p. (Sato et al, 2004). These authors reported focal mild interstitial changes in mice treated with AA-II (Sato et al, 2004).…”

“…AA occurs naturally as a mixture of the structural analogs AA-I and AA-II. To explore the relative nephrotoxic and genotoxic potentials of AA-I or AA-II, we used a mouse model developed by Sato et al (2004).…”

“…These investigators observed impaired growth, increased serum creatinine, glycosuria, tubular proteinuria, and anemia. In addition, Sato et al (2004) observed acute nephrotoxicity and renal interstitial fibrosis in C3H/He and BALB/c mice treated i.p. or p.o.…”

Activation of p53 Promotes Renal Injury in Acute Aristolochic Acid Nephropathy

“…1-3,10 -13 In animals and humans with acute AAN, progressive TEC death with patchy necrosis, primarily affecting proximal TECs in the renal cortex, is the major pathologic feature. 3,10,11,14,15,23 Increased apoptosis has been observed in AA-associated cancers 24 -26 and in cultured tubular cells exposed to AA. 19,27,28 A calcium-dependent mitochondria stress mechanism has been proposed.…”

“…Magnifications: ϫ200 in A through D; ϫ400 in E through F. sis and inflammation in experimental models and patients with acute AAN. 10,14,15 Although apoptosis is an important pathologic feature in in vivo and in vitro studies of acute AAN, 16 -18 the underlying mechanisms remain unclear.…”