RESUMO
Background: Eastern Russell's viper (Daboia siamensis) is one of the most medically significant snakes responsible for the development of acute renal failure. However, variation of the clinical picture and renal pathophysiology following bites by young and adult D. siamensis have not been elucidated. Methods: In this study, we analyzed the venomic profiles of D. siamensis at different maturation stages of juvenile, subadult and adult groups. The same pooled venom from each group was subjected to enzymatic, electrophoretic and proteomic analysis, including sublethal toxicity (0.1 mg/kg iv.) examined on bodily functions by comparing the venom compositional and functional profiles among venom specimens from juvenile, subadult and adult D. siamensis by correlating them with the renal pathophysiology in experimental rabbits. Results: The comparative studies revealed that juvenile venom possessed higher phospholipase A2, metalloproteinase and serine proteinase levels, while subadult and adult venoms contained more L-amino acid oxidase, phosphodiesterase, the Kunitz-type serine protease inhibitor, disintegrin families and endothelial growth factor. An in vivo study revealed that the adult and subadult venoms caused persistent hypotension and bradycardia, while thrombocytopenia was a more characteristic effect of juvenile venom. All venom age groups showed significant reductions in renal hemodynamics and electrolyte excretions. The juvenile venom caused a higher tubulonephrosis lesion score than adult and subadult venoms. Conclusions: The D. siamensis venom shows an ontogenetic shift in its compositions and activities. Renal function alterations after envenomation depend on either the synergistic actions of different venom components or the disproportionate expression between the concentrations of enzymatic and non-enzymatic proteins in each age venom group. The high proportion of enzymatic toxin proteins in the juvenile venom results in greater nephrotoxicity.
RESUMO
Abstract Background: Eastern Russell's viper (Daboia siamensis) is one of the most medically significant snakes responsible for the development of acute renal failure. However, variation of the clinical picture and renal pathophysiology following bites by young and adult D. siamensis have not been elucidated. Methods: In this study, we analyzed the venomic profiles of D. siamensis at different maturation stages of juvenile, subadult and adult groups. The same pooled venom from each group was subjected to enzymatic, electrophoretic and proteomic analysis, including sublethal toxicity (0.1 mg/kg iv.) examined on bodily functions by comparing the venom compositional and functional profiles among venom specimens from juvenile, subadult and adult D. siamensis by correlating them with the renal pathophysiology in experimental rabbits. Results: The comparative studies revealed that juvenile venom possessed higher phospholipase A2 , metalloproteinase and serine proteinase levels, while subadult and adult venoms contained more L-amino acid oxidase, phosphodiesterase, the Kunitz-type serine protease inhibitor, disintegrin families and endothelial growth factor. An in vivo study revealed that the adult and subadult venoms caused persistent hypotension and bradycardia, while thrombocytopenia was a more characteristic effect of juvenile venom. All venom age groups showed significant reductions in renal hemodynamics and electrolyte excretions. The juvenile venom caused a higher tubulonephrosis lesion score than adult and subadult venoms. Conclusions: The D. siamensis venom shows an ontogenetic shift in its compositions and activities. Renal function alterations after envenomation depend on either the synergistic actions of different venom components or the disproportionate expression between the concentrations of enzymatic and non-enzymatic proteins in each age venom group. The high proportion of enzymatic toxin proteins in the juvenile venom results in greater nephrotoxicity.(AU)
Assuntos
Animais , Coelhos/fisiologia , Veias Renais/fisiopatologia , Venenos de Víboras/químicaRESUMO
La hipertensión arterial constituye un problema de salud mundial. Quedan sin esclarecer mecanismos fisiopatogénicos en su aparición. Se ha asociado el bajo peso al nacer por crecimiento intrauterino retardado con la hipertensión en la edad adulta, relacionado con nefrogénesis incompleta. El desarrollo de hipertensión en ratas, provocando hipertrofia tubular proximal, indica que el desbalance entre las funciones glomerular y tubular genera incapacidad excretora del riñón y esta podría existir en el daño renal del bajo peso. Con el objetivo de valorar la posible implicación del desbalance glomérulo-tubular a preponderancia tubular en los mecanismos fisiopatológicos renales descritos en la hipertensión asociada al crecimiento intrauterino retardado, se utilizaron métodos teóricos. El cuerpo teórico elaborado se fundamentó en datos consultados en revistas científicas. Se concluye que el estado de desbalance glomérulo-tubular con preponderancia tubular, ha sido poco estudiado en relación con el desarrollo de la hipertensión en estos sujetos. Este fenómeno no se reconoce, hasta el momento, como una «anormalidad¼ renal, que puede constituir un mecanismo hipertensógeno primario.
High blood pressure (hypertension) is a global health problem. Pathophysiologic mechanisms are unclear in their appearance. Reports have linked low birth weight and intrauterine growth retardation with hypertension in adulthood, related to incomplete nephrogenesis. The development of hypertension in rats leading to proximal tubular hypertrophy indicates that the imbalance between glomerular and tubular functions generates excretory kidney failure and it could be in renal damage of the low weight. In order to assess the possible involvement of glomerular-tubular imbalance with tubular preponderance, within pathophysiological renal mechanisms described in hypertension associated with intrauterine growth retardation, theoretical methods were used. The theoretical framework developed was based on data accessed in scientific journals. We conclude that the state of glomerular-tubular imbalance with tubular preponderance has been little studied in relation to the development of hypertension in these subjects. This phenomenon is not recognized, so far as «abnormal¼ renal, which may be a primary hypertensogenous mechanism.
RESUMO
Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.