Biomedical subjects

Charles L Edelstein

Publications and source records attributed to Charles L Edelstein.

24 records · Page 2Linked to original sources

PubMed2004

Caspase inhibition prevents the increase in caspase-3, -2, -8 and -9 activity and apoptosis in the cold ischemic mouse kidney.

Prolonged cold ischemic time is a risk factor for the development of delayed graft function. The adverse impact of cold ischemia may be associated with tubular cell death in the kidney. Caspase-3 is a major mediator of apoptotic cell death. We hypothesized that caspase inhibition would reduce apoptosis and other features of cold ischemia. Kidneys of C57BL/6 mice were perfused with cold University of Wisconsin solution containing a pancaspase inhibitor or vehicle via the left ventricle. The contralateral right kidney was used as a control. The left kidney was stored for 48 h at 4 degrees C to produce cold ischemia. Caspase-3 activity was massively (100-fold) increased in cold ischemic kidneys compared with controls. On immunoblot analysis, the processed form of caspase-3 was increased in cold ischemic kidneys compared with controls. The increase in caspase-3 was associated with significantly more renal tubular apoptosis and brush-border injury. In addition, caspase-2, -8 and -9 activities were increased in cold ischemic kidneys. The pancaspase inhibitor prevented the formation of the processed form of caspase-3 and the increase in caspase activity, and reduced apoptosis and brush-border injury. Caspase inhibition may prove useful in kidney preservation.

Animals↗

PubMed2003

Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice.

Ischemia/reperfusion (I/R) injury of the kidney is a common cause of acute renal failure (ARF) and is associated with high morbidity and mortality in the intensive care unit. The mechanisms underlying I/R injury are complex. Studies have shown that complement activation contributes to the pathogenesis of I/R injury in the kidney, but the exact mechanisms of complement activation have not been defined. We hypothesized that complement activation in this setting occurs via the alternative pathway and that mice deficient in complement factor B, an essential component of the alternative pathway, would be protected from ischemic ARF. Wild-type mice suffered from a decline in renal function and had significant tubular injury, particularly in the outer medulla, after I/R. We found that factor B-deficient mice (fB(-/-)) developed substantially less functional and morphologic renal injury after I/R. Furthermore, control wild-type mice had an increase in tubulointerstitial complement C3 deposition and neutrophil infiltration in the outer medulla after I/R, whereas fB(-/-) mice demonstrated virtually no C3 deposition or neutrophil infiltration. Our results demonstrate that complement activation in the kidney after I/R occurs exclusively via the alternative pathway, and that selective inhibition of this pathway provides protection to the kidneys from ischemic ARF.

Acute Kidney Injury↗

PubMed2002

Caspases, Bcl-2 proteins and apoptosis in autosomal-dominant polycystic kidney disease.

BACKGROUND: Apoptosis is a characteristic feature of human autosomal-dominant polycystic kidney disease (ADPKD). The Han:Sprague-Dawley (SPRD) rat model closely resembles human ADPKD and presents an opportunity to investigate the apoptotic pathway in the pathogenesis of this disease. METHODS: Han:SPRD rats were studied during the early stages of ADPKD (newborn, 2 and 6 weeks old). Apoptotic cells were detected by the TUNEL (Tdt-mediated dUTP nick end-labeling) assay. Caspase-3 activity was measured using the fluorescent substrate DEVD-AMC and cleavage of poly (ADP-ribose) polymerase [PARP]. Expression of pro- and anti-apoptotic B-cell lymphoma (Bcl-2) proteins was detected on Western blot analysis. RESULTS: TUNEL (+) cells, caspase-3 activity and caspase-mediated PARP breakdown were significantly increased in 2-week-old heterozygous (Cy/+) and homozygous (Cy/Cy) rat kidneys compared to normal littermate controls. In Cy/+ rat kidneys, decreased expression of anti-apoptotic Bcl-XL coincided with increased caspase-3 activity at 2 weeks of age while expression of Bcl-2, another anti-apoptotic protein, increased at 6 weeks of age. In Cy/Cy rat kidneys, decreased expression of Bcl-XL and increased expression of Bcl-2 was present at 2 weeks of age. Pro-apoptotic Bax and Bad expression was unchanged at 2 weeks of age in both Cy/+ and Cy/Cy rat kidneys. CONCLUSIONS: Activation of caspase-3 and dysregulation of the balance between pro- and anti-apoptotic Bcl-2 family members, specifically a down-regulation of anti-apoptotic Bcl-XL, correlates with increased apoptosis in polycystic Han:SPRD rat kidneys.

Animals↗

PubMed2002

Protective effect of renal denervation on normotensive endotoxemia-induced acute renal failure in mice.

Acute renal failure (ARF) contributes substantially to the high morbidity and mortality observed during endotoxemia. We hypothesized that selective blockade of the renal nerves would be protective against ARF during the early (16 h) stage of endotoxemia [5 mg lipopolysaccharide (LPS)/kg ip in mice]. At 16 h after LPS, there was no change in mean arterial pressure, but plasma epinephrine (4,604 +/- 719 vs. 490 +/- 152 pg/ml, P < 0.001), norepinephrine (2,176 +/- 306 vs. 1,224 +/- 218 pg/ml, P < 0.05), and plasma renin activity (40 +/- 5 vs. 27 +/- 2 ng x ml(-1) x h(-1), P < 0.05) were higher in the LPS-treated vs. control mice. The high plasma renin activity level decreased to the control level with renal denervation in endotoxemic mice. After intravenous injection of phentolamine (200 microg/kg), the decrement in mean arterial pressure was significantly greater in LPS-treated vs. control mice (19.4 +/- 3.5 vs. 8.1 +/- 1.5 mmHg, P < 0.01). Sixteen hours after LPS administration, there were significant decreases in glomerular filtration rate (52 +/- 18 vs. 212 +/- 23 microl/min, P < 0.01) and renal blood flow (0.58 +/- 0.08 vs. 0.85 +/- 0.06 ml/min, P < 0.01) in sham-operated mice. The decrement in glomerular filtration rate during endotoxemia was significantly attenuated in mice with denervated kidneys (32 vs. 79%). Moreover, there was no change in renal blood flow during endotoxemia in mice with renal denervation. The present results therefore demonstrate a protective role of renal denervation during normotensive endotoxemia-related ARF in mice, an effect that may be, at least in part, due to a diminished activation of the renin-angiotensin system.

Acute Kidney Injury↗

PubMed2002

Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice.

Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH(2)-OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evaluate whether this lack of neutrophil infiltration was contributing to the protection against ischemic ARF, a model of neutrophil depletion was developed. Neutrophil-depleted mice had a small (18%) reduction in serum creatinine during ischemic ARF but no reduction in ATN score despite a lack of neutrophil infiltration in the kidney. Remarkably, caspase-1 activity and IL-18 were significantly increased in the kidney in neutrophil-depleted mice with ARF. In addition, IL-18 antiserum-treated neutrophil-depleted mice with ischemic ARF had a significant (75%) reduction in serum creatinine and a significant reduction in ATN score compared with vehicle-treated neutrophil-depleted mice. These results suggest a novel neutrophil-independent mechanism of IL-18-mediated ischemic ARF.

Amino Acid Chloromethyl Ketones↗

PubMed2000

Desensitization of soluble guanylate cyclase in renal cortex during endotoxemia in mice.

Acute endotoxemic renal failure involves renal vasoconstriction, which presumably occurs despite increased nitric oxide (NO) generation by inducible NO synthase in the kidney. The present study examined the hypothesis that the renal vasoconstriction during endotoxemia occurs in part because of desensitization of soluble guanylate cyclase (sGC). Endotoxic shock was induced in male B6/129F2/J mice by an intraperitoneal injection of Escherichia coli lipopolysaccharide. The endotoxemia resulted in shock and renal failure as evidenced by a decrease in mean arterial pressure and an increase in serum creatinine and urea nitrogen. Serum NO increased in a time-dependent manner, reaching the highest levels at 24 h, in parallel with induction of inducible NO synthase protein in the renal cortex. In renal cortical slices obtained from endotoxemic mice, cyclic guanosine monophosphate (cGMP) increased significantly at 6 h and 15 h as compared with control but normalized at 24 h after injection of lipopolysaccharide. Incubation of renal cortical slices in the presence of a phosphodiesterase inhibitor isobutylmethylxantine did not alter the pattern of changes in cGMP. Incubation of renal cortical slices with 2 mM sodium nitroprusside resulted in a similar accumulation of cGMP in slices taken from control and endotoxemic mice at 6 h and 15 h. However, in slices from 24-h endotoxemic mice, accumulation of cGMP in response to sodium nitroprusside was significantly lower. This lower stimulability of sGC was not paralleled by a decrease in its abundance in renal cortex on immunoblot. Taken together, these results demonstrate a desensitization of sGC in renal cortex during endotoxemia, which may contribute to the associated renal vasoconstriction.

Acute Kidney Injury↗