Endothelin up-regulation and localization following renal ischemia and reperfusion. (1/222)

BACKGROUND: Endothelin (ET), a potent vasoconstrictor, is known to play a role in ischemic acute renal failure. Although preproET-1 (ppET-1) mRNA is known to be up-regulated following ischemia/reperfusion injury, it has not been determined which component of the injury (ischemia or reperfusion) leads to initial gene up-regulation. Likewise, although ET-1 peptide expression has been localized in the normal kidney, its expression pattern in the ischemic kidney has not been determined. Therefore, the purpose of this study was twofold: (a) to determine whether ischemia alone or ischemia plus reperfusion is required for the up-regulation of ppET-1 mRNA to occur, and (b) to localize ET-1 peptide expression following ischemia in the rat kidney to clarify better the role of ET in the pathophysiology of ischemia-induced acute renal failure. METHODS: Male Lewis rats underwent clamping of the right renal vascular pedicle for either 30 minutes of ischemia (group 1), 60 minutes of ischemia (group 2), 30 minutes of ischemia followed by 30 minutes of reperfusion (group 3), or 60 minutes of ischemia followed by three hours of reperfusion (group 4). The contralateral kidney acted as a control. ppET-1 mRNA up-regulation and ET-1 peptide expression were examined using the reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Reverse transcription-polymerase chain reaction yielded a control (nonischemic) value of 0.6 +/- 0.2 densitometric units (DU) of ppET-1 mRNA in the kidney. Group 1 levels (30 min of ischemia alone) were 1.8 +/- 0.4 DU, a threefold increase (P < 0.05). Group 2 levels (60 min of ischemia alone) increased almost six times above baseline, 3.5 +/- 0.2 DU (P < 0.01), whereas both group 3 and group 4 (ischemia plus reperfusion) did not experience any further significant increases in mRNA levels (1.9 +/- 0.4 DU and 2.8 +/- 0.6 DU, respectively) beyond levels in group 1 or 2 animals subjected to similar ischemic periods. ET-1 peptide expression in the ischemic kidneys was significantly increased over controls and was clearly localized to the endothelium of the peritubular capillary network of the kidney. CONCLUSIONS: Initial ET-1 gene up-regulation in the kidney occurs secondary to ischemia, but reperfusion most likely contributes to sustaining this up-regulation. The marked increase of ET-1 in the peritubular capillary network suggests that ET-induced vasoconstriction may have a pathophysiological role in ischemic acute tubular necrosis.  (+info)

Comparative nephrotoxicities of netilmicin and gentamicin in rats. (2/222)

The relative nephrotoxicities of netilmicin (Sch 20569) and gentamicin were compared in rats at doses of 30, 60, 90, and 120 mg/kg per day for 15 days. Both drugs caused proteinuria and a decrease in urine osmolality; however, netilmicin produced significantly less changes at all doses than gentamicin. Whereas gentamicin resulted in a decline in creatinine clearance at all doses, netilmicin failed to cause a decline in creatinine clearance. Renal-cortical concentrations of antibiotic at sacrifice were similar in animals receiving either drug. Light-microscopic changes were less severe with netilmicin than gentamicin. Cytosegresomes with myeloid bodies were identified electron microscopically in the kidneys of animals receiving either netilmicin or gentamicin at all doses. Electron-microscopic manifestations were similar. The data indicate that in the rat, netilmicin is distinctly less nephrotoxic than gentamicin.  (+info)

Regeneration of renal proximal tubules after mercuric chloride injury is accompanied by increased binding of aminoacyl-transfer ribonucleic acid. (3/222)

Homogenates of rat kidney cortex obtained 1,3 or 14 days after a single injection of HgCl2 were used to prepare the post-microsomal pH5 supernatant fraction. The activity of this fraction for peptide synthesis from [14C]phenylalanyl-tRNA was significantly increased at 1 and 3 days, at which time the proximal tubules are regenerating [Cuppage & Tate (1967) Am. J. Pathol. 51, 405-429]. This increased activity could not be attributed to a decreased inhibitory activity, but was due to an increased aminoacyl-tRNA binding, i.e. elongation-factor-1 activity, in the supernatant fraction.  (+info)

Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo. (4/222)

We have shown previously that gamma-glutamyl transpeptidase (GGT) activity is essential for the nephrotoxicity of cisplatin. In this study we asked whether GGT activity was necessary for the antitumor activity of cisplatin. GGT was transfected into PC3 cells, a human prostate tumor cell line. Two independent GGT-positive cell lines were isolated and characterized. GGT cleaves extracellular glutathione providing the cells with access to additional cysteine. Expression of GGT had no effect on the growth rate of the cells in vitro where the culture medium contains high levels of cysteine. However, when the cells were injected into nude mice the GGT-positive tumors grew at more than twice the rate of the GGT-negative tumors. Weekly treatment with cisplatin was toxic to both GGT-positive and -negative tumors. The GGT-positive tumors were significantly more resistant to the toxicity of cisplatin than the GGT-negative tumors. Therefore, expression of GGT is required for the nephrotoxicity of cisplatin, but diminishes the tumor toxicity of the drug. These results indicate that the nephrotoxicity and the tumor toxicity of cisplatin are via two distinct pathways.  (+info)

Acute renal failure in the course of HIV infection: a single-institution retrospective study of ninety-two patients anad sixty renal biopsies. (5/222)

BACKGROUND: Acute renal failure syndromes are frequently encountered in patients with human immunodeficiency virus (HIV) infection. Most reported cases of acute renal failure are related to acute tubular necrosis, but many other causes of renal failure have been described in these patients. METHODS: The present work is a single-institution retrospective study of 92 HIV-infected patients with acute or rapidly progressing renal failure. In 60 cases, a renal biopsy was performed. For each patient we analysed clinical and pathological data, as well as the short-term prognosis. RESULTS: Ten different causes of acute or rapidly progressing renal failure were documented: (i) haemolytic uraemic syndrome (32 patients); (ii) acute tubular necrosis either of ischaemic-toxic origin (18 patients) or due to rhabdomyolysis (six patients); (iii) obstructive renal failure which was either extrinsic (two patients), drug-induced (13 patients) or secondary to paraprotein precipitation (one patient); (iv) HIV-associated nephropathy (14 patients); (v) acute interstitial nephritis (two patients); (vi) various glomerulonephritis (four patients). In most cases, renal failure was severe (the mean creatinine clearance at entry was 12 ml/min). Most patients had a significant improvement in renal function with only symptomatic treatment. Eighteen per cent of the patients died within 2 months of the diagnosis of renal failure. Renal biopsy seems important for the diagnosis but also for the prognosis, at least in the cases of haemolytic-uraemic syndrome, HIV-associated nephropathy and drug-induced micro-obstructive renal failure. CONCLUSION: Vascular and glomerular diseases are frequent causes of acute or rapidly progressing renal failure in HIV-infected patients. Renal biopsy appears to be safe and useful for the diagnosis and the prognosis of the renal failure. High mortality rate is only observed in patients with ischaemic/toxic causes of acute renal failure.  (+info)

Molecular mechanisms of renal hypertrophy: role of p27Kip1. (6/222)

There are two fundamentally different growth responses for cells comprising the nephron: hyperplasia or hypertrophy. Cells that progress through the normal cell cycle double their DNA content and eventually divide during mitosis. Those cells that hypertrophy stop the growth process in the G1-phase of the cell cycle; while they increase in size, protein and RNA content, they cannot duplicate their set of chromosomes because they never pass through the S-phase of the cell cycle. Hypertrophy may be an early compensatory mechanism to initially replace the loss of functioning tissue, however, this maladaptive process eventually fosters progressive loss of renal function. Since progression of the cell through the G1 to S-phases is regulated by cyclins D, E and A, which in turn bind and activate cyclin dependent kinases (CDKs), evidence has been accumulating on a particular CDK-inhibitor protein, p27Kip1, which is speculated to be a key to the complex process of the G1/S cell cycle transition. This article examines the mechanisms of the proliferative growth response following acute tubular necrosis, and compensatory hypertrophy of glomerular and tubule cells, with a particular focus on the protein p27Kip1.  (+info)

Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1. (7/222)

BACKGROUND: The transcription factor Pax-2 is known to play a key regulatory role during embryonic development of the nervous and excretory systems in mammals and flies. During mouse kidney development, Pax-2 is expressed in the undifferentiated mesenchyme in response to ureter induction and continues to be expressed in the developing comma- and s-shaped bodies. These structures harbor the immediate precursors of the proximal tubular epithelial cells. Pax-2 expression is down-regulated as the differentiation of the functional units of the nephron proceeds. In the adult mammalian kidney, the Pax-2 protein is detectable exclusively in the epithelium of the collecting ducts. We sought to test the hypothesis that tissue regeneration is characterized by re-expression of developmentally important regulatory genes such as Pax-2. METHODS: The expression pattern of Pax-2 in kidneys after experimentally-induced acute tubular necrosis caused by intraperitoneally injected folic acid in mice was tested by indirect immunofluorescence, Western blotting, reverse transcriptase-polymerase chain reaction, and in situ hybridization analysis. RESULTS: A transient, temporally and locally restricted re-expression of Pax-2 in regenerating proximal tubular epithelial cells was observed following kidney damage. CONCLUSIONS: These data indicate that during the regeneration processes, developmental paradigms may be recapitulated in order to restore mature kidney function.  (+info)

Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable. (8/222)

Acute renal failure (ARF) due to ischemic or toxic renal injury, a clinical syndrome traditionally referred to as acute tubular necrosis (ATN), is a common disease with a high overall mortality of approximately 50%. Little progress has been made since the advent of dialysis more than 30 years ago in improving this outcome. During this same period, a considerable amount of basic research has been devoted to elucidating the pathophysiology of ATN. The ultimate goal of this research is to facilitate the development of therapeutic interventions that either prevent ARF, ameliorate the severity of tubular injury following an acute ischemic or toxic renal insult, or accelerate the recovery of established ATN. This research endeavor has been highly successful in elucidating many vascular and tubular abnormalities that are likely to be involved in ischemic and toxic ARF. This information has led to impressive advances in the development of a number of different pharmacological interventions that are highly effective in ameliorating the renal dysfunction in animal models of ARF. Although these developments are exciting and promising, enthusiasm of investigators involved in this endeavor has been tempered somewhat by the results of a few recent clinical studies of patients with ATN. These trials, designed to examine the efficacy in humans of some of the interventions effective in animal models of ARF, have resulted in little or no benefit. This is therefore an important time to reevaluate the approaches we have taken over the past three to four decades to develop new and effective treatments for ATN in humans. The major goals of this review are 1) to evaluate the relevance and utility of the experimental models currently available to study ischemic and toxic renal injury, 2) to suggest novel experimental approaches and models that have the potential to provide advantages over methods currently available, 3) to discuss ways of integrating results obtained from different experimental models of acute renal injury and of evaluating the relevance of these findings to ATN in humans, and 4) to discuss the difficulties inherent in clinical studies of ATN and to suggest how studies should be best designed to overcome these problems.  (+info)