The pathophysiological effects of Russell's viper (Daboia siamensis) venom and its fractions in the isolated perfused rabbit kidney model: A potential role for platelet activating factor

Abstract

The pathophysiological effects of Russell's viper venom (RVV) and its fractions, including phospholipase A 2 (RvPLA 2 ), metalloprotease (RvMP), L-amino acid oxidase (RvLAAO), and phosphodiesterase (RvPDE) on renal functions were investigated using the isolated perfused rabbit kidney (IPK) model. Moreover, whether their effects on renal alterations were promoted by platelet activating factor (PAF) was tested using the PAF receptor antagonist, WEB 2086. There was a marked reduction in the perfusion pressure (PP) and renal vascular resistance (RVR) 10 min after RVV administration (1.0 mg/100 ml of perfusate), thereafter both PP and RVR gradually increased and approached the control level within 90 min. These effects were abolished by pretreatment with WEB2086 (2 μg/μl). Administration with RvPLA 2 (280 μg/ml), RvMP (280 μg/ml), or RvLAAO (135 μg/ml) alone increased both the PP and RVR, whereas RvPDE (100 μg/ml) reduced both the PP and RVR. Pretreatment with WEB 2086 completely abolished the effects induced by RvMP, but not the other fractions. The RVV also caused a marked decrease in the glomerular filtration rate (GFR), urinary flow rate (UF), and osmolar clearance (Cosm), and these effects were not inhibited by pretreatment with WEB2086. Each RVV fraction also increased, to varying extents, the GFR, UF, and Cosm, and these effects induced by RvPLA 2 or RvMP, but not the other fractions, were completely blocked by WEB 2086. Changes in percent filtered Na + and K + excreted in the IPK by RVV, RvPDE, and RvMP were abolished by pretreatment with WEB 2086. Histological evaluation profiled mainly tubulonephrosis in the treated kidney. These results reveal that the alterations in renal functions induced by RVV and its fractions are due to the synergistic action of the different components of snake venom, instead of the action of a single component. The effects of RVV and its fractions in rabbit IPK are mediated at least in part by PAF.

A Biochemical and Pharmacological Characterization of Phospholipase A2 and Metalloproteinase Fractions from Eastern Russell’s Viper (Daboia siamensis) Venom: Two Major Components Associated with Acute Kidney Injury

“…In the current study, we determined histopathological changes of mouse kidneys following intraperitoneal administration of venom or fractions (300 µg/kg) for 24 h. A moderate degree of histopathological lesions was detected as diffuse and/or focal glomeruli, and congestion of interstitial vessels and tubular injury. These are almost the same characteristics of kidney lesion as identified in previous studies using perfused rabbit kidneys [ 21 ] and rat in vivo experiments [ 27 ]. However, the degree of morphological changes observed in our present work could not be compared with previous work performed by our group due to the differences in species of experimental animal used and time of contact with venom or toxins.…”

“…Isolation and Purification of RvPLA 2 and RvMP were completed as previously described [ 21 ]. In brief, for RvPLA 2 isolation, D. siamensis venom (DSV) was fractionated using HiTrap CM FF ion-exchange column and the elution chromatogram yielded three major peaks ( Figure 1 A).…”

“…A recent study, using an ex vivo perfused rabbit kidney model, showed that RvPLA 2 and RvMP (280 µg/mL) significantly increased perfusion pressure, urinary flow rate, glomerular filtration rate, osmolar clearance, and renal vascular resistance [ 21 ]. Histopathological determination of perfused rabbit kidney sections revealed crystal deposits in the glomerular capillary lumen, dilatation of proximal and distal convoluted tubules, as well as tubulonephrosis, following incubation with RvPLA 2 or RvMP for 90 min.…”

“…The degree of histopathologic change observed following snake envenoming is significantly associated with the time of contact with venom or toxin [ 28 ]. The effects of RvPLA 2 and RvMP on physiological function and morphological changes were abolished by the prior addition of the platelet activating factor (PAF) inhibitor, WEB 2086 [ 21 ]. This suggests a role for PAF to modulate glomerular functions via PAF receptor within the renal glomeruli [ 29 ].…”

“…Recently, RvPLA 2 and RvMP were isolated from D. siamensis venom and showed physiological function and histopathological changes in ex vivo perfused rabbit kidney model after incubation for 9 h [ 21 ]. However, potential contributing factors following administration of RvPLA 2 and RvMP, for example, myotoxicity involvement, the effects of purified fractions in an in vivo model extending beyond 9 h, and their roles in the mechanism of AKI have not been fully investigated.…”