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Much effort has been made in recent years to clarify metabolic and renal function changes in sepsis. A number of studies performed in different models of sepsis have been described. One such model that is frequently used is cecal ligation and puncture (CLP) in rats. This model resembles human sepsis in several important aspects, such as an early phase of hyperdynamic, hypermetabolic sepsis followed by a late hypodynamic, hypometabolic phase. The present study evaluated the blood pressure (n = 5) and renal function changes during development of CLP renal failure and to determine the effects of NOS inhibition (L-NAME) and 0.15 M NaCl administration on tail blood pressure and renal function in randomly assigned five groups (n = 10 each): (1) Sham-operated, (2) Sham-operated L-NAME-treated, (3) CLP rats, (4) CLP L-NAME-treated, and (5) CLP 0.15 M NaCl-treated rats. The basal tail blood pressure was not significantly different among the four groups. One week later, arterial pressure was significantly increased in sham-operated L-NAME-treated rats (159 +/- 12 mmHg) compare with the other groups (118 +/- 9.0 mmHg in nontreated rats, p < 0.05). Blood pressure shows a slightly and not significant decrease up to 12h in L-NAME and 0.15 M NaCl treated rats, which in turn was followed by a significant reduced arterial pressure 18h after CLP in both groups (L-NAME: 96.0 +/- 3.6 mmHg, p < 0.05) and NaCl: 82.3 +/- 2.4 mmHg, p < 0.05) compared to sham-operated groups. The glomerular filtration rate estimated by CCr decreases significantly in the CLP untreated group (p < 0.001) and did not significantly differ from the sham-operated and L-NAME-treated groups (p = 0.4) during the studies of renal tubule sodium handling. On the other hand, subcutaneous 0.15 M NaCl administration prevented CCr decreases in CLP rats (p = 0.25). CLP increased the FENa in the sham-operated from: 857.2 +/- 85.1 delta%min(-1) to CLP: 1197.8 +/- 119.0 delta%min(-1). The high FENa to CLP was blunted and significantly reduced by previous systemic treatment of animals with L-NAME from sham-operated+L-NAME: 1368.0 +/- 72.0 delta%min(-1) to CLP+L-NAME: 1148.0 +/- 60.4 delta%min(-1) (p < 0.01). The enhanced FENa in the CLP group were accompanied by a significant increase in proximal sodium reabsorption rejection. The salient findings of the present study suggest that a decrease in the blood pressure and creatinine clearance caused by CLP may benefit from L-NAM and fluid resuscitation during initial bacteremia (first 12 h) by promoting an additional increase of tubule sodium reabsorption in the post-proximal segments of nephrons, but these therapies could not prevent acute renal failure after established endotoxemia.

The venom of Bothrops moojeni has potent proteolytic and phospholipase A2 activities. In previous work, we showed that intravenous injection of this venom in rats decreased creatinine clearance and caused tubular dysfunction and histopathological changes with no alterations in blood pressure. The current study used scanning and transmission electron microscopy to assess the ultrastructural changes caused by B. moojeni venom (0.4 mg/kg i.v.) in rat renal glomeruli and correlated these alterations with the severity of proteinuria 5 hours, 16 hours, and 48 hours after venom injection. The changes included mesangiolysis, glomerular microaneurysms, and glomerular basement membrane (GBM) abnormalities. In addition, there was a reduction in the number and width of podocyte pedicels, which caused a reduction in the number of filtration slits. Electron-dense amorphous material, which may be proteinaceous in origin, was found in the pedicels. The severity of the ultrastructural abnormalities correlated with the level of proteinuria. These morphophysiological changes were attributed to biochemical and physiological disturbances in the components of the GBM and mesangial matrix as well as in cytoskeleton-associated proteins of podocytic processes, and could account for the breakdown of optimal glomerular filtration barrier functioning. These results, together with the absence of appreciable glomerular fibrin deposits, support the hypothesis of a direct activity of B. moojeni venom on rat kidneys. Proteolytic activity of the venom on renal glomeruli could then contribute to the onset of acute renal failure, and would explain the clinical manifestations of renal injury after bites by this and other Bothrops species.

Aims/hypothesis: To investigate the interaction between hypertension and diabetic nephropathy, we studied the renal accumulation of fibronectin in a genetic model of hypertension with streptozotocin-induced diabetes mellitus., Methods: Spontaneously hypertensive rats (SHR) and their genetically normotensive control Wistar Kyoto rats (WKY) were studied at 4 weeks of age. The rats were killed 20 days after the induction of diabetes mellitus. The renal accumulation of fibronectin was estimated using Western blot analysis as well as immunofluorescence technique and confocal microscopy., Results: Blood glucose concentrations were similar in diabetic SHR rats (27 +/- 3.3 mmol/l) and WKY rats (25.5 +/- 2.7 mmol/l). The systolic blood pressure was higher in both groups of SHR rats than in the control rats. The abundance of renal fibronectin as detected by Western blot analysis was (p < 0.05) higher in the diabetic SHR rats (41.4 +/- 15.0 densitometric U, n = 8) than in the control rats, and no difference was observed between diabetic and control WKY rats (20.8 +/- 6.2, n = 8) and (27.8 +/- 17.2, n = 8). The mean peak intensity of fibronectin signal within the glomerulus as estimated by confocal microscopy was higher (p < 0.05) in the diabetic SHR rats (32.9 +/- 3.5) than in control SHR rats (11.9 +/- 5.7) or diabetic (7.4 +/- 2.2) and control (15.2 +/- 7.9) WKY rats., Conclusion/interpretation: In experimental diabetes the presence of genetic hypertension promotes earlier accumulation of renal fibronectin, a matrix protein implicated in renal glomerulosclerosis.

Acute renal failure (ARF) is the main cause of death following snake bites by Bothrops species. In this study, we investigated the morphologic and functional renal disturbances caused by Bothrops moojeni venom in rats. Renal function was assessed based on creatinine and lithium clearances and on histologic examination of renal tissue 5 hr after the intravenous administration of 0.2 mg of venom/kg and 5 hr, 16 hr, and 48 hr after 0.4 mg of venom/ kg. A venom dose of 0.4 mg/kg produced renal tubule disturbances, including acute impairment of proximal and post-proximal tubule sodium handling associated with acute tubule necrosis. The glomerular filtration rate (GFR) decreased significantly and was accompanied by severe morphologic disturbances in the renal glomeruli. These functional and morphologic findings were observed in the absence of any change in mean arterial blood pressure. The decrease in GFR was not related to the presence of fibrin deposits in the glomerular capillary loops. These results suggest an early nephrotoxic action of B. moojeni venom involving significant morphologic and functional changes similar to those observed in snakebite-induced ARF in humans.