Temporal induction of clusterin in cisplatin nephrotoxicity.

1997 ◽  
Vol 8 (2) ◽  
pp. 302-305
Author(s):  
J R Silkensen ◽  
A Agarwal ◽  
K A Nath ◽  
J C Manivel ◽  
M E Rosenberg
Keyword(s):  
Serum Creatinine ◽  
Time Course ◽  
Tissue Injury ◽  
Kidney Tissue ◽  
Sprague Dawley ◽  
Outer Medulla ◽  
Creatinine Concentration ◽  
Cisplatin Nephrotoxicity ◽  
Tubular Necrosis ◽  
Outer Stripe

Clusterin is a ubiquitous glycoprotein induced in many organs, including the kidney, at times of tissue injury and/or remodeling. It is speculated in this study that clusterin preserves cell interactions that are otherwise perturbed by renal insults. The purpose of this study was to examine clusterin expression after cisplatin nephrotoxicity, a model characterized by a delayed time course of injury and a well-defined site of that injury (proximal tubule). Sprague-Dawley rats were treated with intravenous cisplatin (6 mg/kg) or vehicle. Serum creatinine concentrations were measured and kidneys harvested at 1, 2, and 5 days. Marked induction of clusterin mRNA was seen only at 5 days, a time when serum creatinine concentration was the highest. Histology of kidney tissue 5 days after cisplatin administration revealed marked tubular necrosis localized to the outer stripe of the outer medulla, a region rich in proximal tubules. Immunohistochemistry and in situ hybridization at 5 days demonstrated clusterin primarily in the inner stripe of the outer medulla. In conclusion, expression of clusterin follows renal injury with cisplatin at a time corresponding to the morphologic evidence of tubular necrosis and cell detachment; quite surprisingly, such expression occurs at a site distant from the primary injury.

Endogenous EGF as a potential renotrophic factor in ischemia-induced acute renal failure

1993 ◽  
Vol 265 (3) ◽  
pp. F425-F434 ◽  
Author(s):  
R. P. Schaudies ◽  
D. Nonclercq ◽  
L. Nelson ◽  
G. Toubeau ◽  
J. Zanen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Time Course ◽  
Tissue Injury ◽  
Cell Turnover ◽  
Paraffin Sections ◽  
Outer Medulla ◽  
New Synthesis ◽  
Predominant Form ◽  
Outer Stripe ◽  
Epidermal Growth

The time course for the increases in soluble renal epidermal growth factor (EGF) after ischemia has been established. These elevated levels of EGF have been compared with the degree of tissue injury as well as the extent of cell proliferation in the recovering tissue. Levels of soluble immunoreactive EGF (irEGF) in control animals were 9.74 +/- 1.1 ng/g wet wt (n = 4-8 for all values) and rose to 83.9 +/- 30 ng/g within 12 h after injury. Soluble irEGF content peaked at 88.8 +/- 15 ng/g at 24 h postinjury and returned to control values by 72 h. We previously reported that trypsin digestion of crude renal membranes (CRM) generates rat EGF that is indistinguishable from that isolated from the submandibular gland. Initial levels of trypsin-releasable membrane-associated irEGF were 439 +/- 26 ng/g. These levels fell to 46.6 +/- 9.6 ng/g at 48 h after injury. The total renal EGF demonstrated an 80% decline 48 h after injury but returned to 50% of the initial values after 72 h representing significant new synthesis of EGF-containing proteins between 48 and 72 h postinjury. Immunohistochemical staining of kidney paraffin sections for EGF immunoreactivity demonstrated staining intensities that paralleled the amount of irEGF in the trypsin-digested CRM fraction, suggesting that the membrane-associated irEGF is the predominant form detected by this technique. Regenerative hyperplasia subsequent to tubular insult was monitored by immunostaining nuclei of S phase cells after pulse labeling with the thymidine analogue 5-bromo-2'-deoxyuridine. Cell proliferation was particularly prominent in the outer stripe of outer medulla of kidneys exposed to ischemia and reached a maximum (19-fold higher than the baseline value) 48 h after reperfusion. Renal cell turnover returned to control values by day 7. The observation that the peak in soluble EGF levels (24 h) precedes the peak in tubular regeneration (48 h) by 24 h is consistent with the hypothesis that EGF is one of the mitogenic signals triggering regenerative hyperplasia after renal injury.

Protective Effect of Prostaglandin [PGE2] in Glycerol-Induced Acute Renal Failure in Rats

1978 ◽  
Vol 55 (5) ◽  
pp. 505-507 ◽  
Author(s):  
R. Werb ◽  
W. F. Clark ◽  
R. M. Lindsay ◽  
E. O. P. Jones ◽  
D. I. Turnbull ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Serum Creatinine ◽  
Prostaglandin E2 ◽  
Serum Creatinine Concentration ◽  
Sprague Dawley ◽  
Glomerular Permeability ◽  
Creatinine Concentration ◽  
Significant Difference ◽  
Group B

1. Acute renal failure was induced in female Sprague—Dawley rats by the subcutaneous injection of glycerol. 2. Four groups of rats were studied; all animals received a glycerol challenge. Group A (control) were sham-operated only, group B received an infusion of sodium chloride solution (150 mmol/l; saline) for 24 h, group C received an infusion containing prostaglandin E2 (PGE2, 1.7 μmol/l) in saline and group D a solution containing PGE2 (3.4 μmol/l) in saline. 3. All rats were killed 48 h after glycerol challenge. The degree of renal impairment was assessed by serum creatinine concentration, which did not differ in sham-operated animals and the group receiving saline alone. The group of rats receiving the lower dose of PGE2 has a significantly lower mean serum creatinine concentration than the saline-infused control rats (P < 0.0025). Creatinine concentration was further lowered by the higher dose of PGE2 but there was not a significant difference in the number of rats showing severe tubular necrosis histologically. 4. The study demonstrates that intravenous infusion of prostaglandin E2 has a protective influence on glycerol-induced renal failure in the rat; the protection afforded may be due to the vasodilator effect of PGE2 and/or an effect on glomerular permeability.

Kidney protection by pretreatment with free radical scavengers and allopurinol: Renal function at recirculation after warm ischaemia in rabbits

1986 ◽  
Vol 71 (3) ◽  
pp. 245-251 ◽  
Author(s):  
R. Hansson ◽  
S. Johansson ◽  
O. Jonsson ◽  
S. Pettersson ◽  
T. Scherstén ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Renal Function ◽  
Serum Creatinine ◽  
Kidney Tissue ◽  
Urine Osmolality ◽  
Free Radical Scavengers ◽  
Control Group ◽  
Creatinine Concentration ◽  
Pronounced Increase ◽  
Before And After

1. Renal function and morphology were studied before and after 60 min of renal ischaemia and contralateral nephrectomy in five groups of rabbits. The animals were pretreated with superoxide dismutase, catalase, allopurinol or mannitol. One group was not pretreated and served as a control. 2. A moderate transient increase in serum creatinine concentration was observed in the control rabbits, while a significantly less pronounced increase was noted after pretreatment with superoxide dismutase, catalase and mannitol. 3. Pretreatment with allopurinol did not significantly reduce the postoperative increase in serum creatinine and sodium excretion, but the urine osmolality returned to normal more rapidly than in the control group. 4. The appearance under the light microscope of kidney tissue taken from surviving rabbits was found to be normal irrespective of pretreatment. Severe tubular necrosis was observed in the kidneys from rabbits that died during the observation period.

Time course of renal glutamate dehydrogenase induction during NH4Cl loading in rats

1992 ◽  
Vol 262 (6) ◽  
pp. F999-F1006 ◽  
Author(s):  
P. A. Wright ◽  
R. K. Packer ◽  
A. Garcia-Perez ◽  
M. A. Knepper
Keyword(s):  
Glutamate Dehydrogenase ◽  
Time Course ◽  
Renal Cortex ◽  
Ammonium Excretion ◽  
Mrna Levels ◽  
Outer Medulla ◽  
Acid Intake ◽  
Blood Ph ◽  
Outer Stripe ◽  
Acid Loading

To study mechanisms involved in renal glutamate dehydrogenase (GDH) regulation in response to systemic acid loading, we have measured blood pH, ammonium excretion, renal GDH mRNA levels, and GDH activity in rats. Acid intake (0.28 M NH4Cl in drinking water for 3 days) increased GDH mRNA levels in the renal cortex, but had no effect in the outer stripe of the outer medulla, inner stripe of the outer medulla, or the inner medulla. Rats were subjected to a step change in acid intake by alkali loading for 3 days (7.2 meq NaHCO3 per day in food slurry) and shifting to acid loading for up to 7 days (7.2 meq NH4Cl in food slurry). Ammonium excretion rose rapidly, increasing by 14-fold in the first 24-h period and 38-fold in the second 24-h period. Cortical GDH mRNA levels were increased relative to alkali-loaded values by 3.7-fold in 24 h, 4.3-fold in 4 days, but only 2.2-fold in 7 days. GDH activity was unchanged after 24 h of acid intake, but was significantly increased after 48 h. We concluded the following: 1) GDH mRNA is present in all regions of the kidney, but levels increase in response to acid loading only in the renal cortex; 2) GDH mRNA levels increase within 1 day after the initiation of acid loading, but the associated increase in functional enzyme activity takes 2 or more days; and 3) the large increases in ammonium excretion that occur in the first day after initiation of acid loading are not dependent on increased GDH activity.

Epidermal growth factor accelerates functional recovery from ischaemic acute tubular necrosis in the rat: Role of the epidermal growth factor receptor

1990 ◽  
Vol 78 (5) ◽  
pp. 445-450 ◽  
Author(s):  
Jill Norman ◽  
Yong-Kwei Tsau ◽  
Angelito Bacay ◽  
Leon G. Fine
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Serum Creatinine ◽  
Acute Tubular Necrosis ◽  
Growth Factor Receptor ◽  
Serum Creatinine Concentration ◽  
Creatinine Concentration ◽  
Tubular Necrosis ◽  
Epidermal Growth ◽  
Exogenous Epidermal Growth Factor

1. Severe, ischaemic, acute tubular necrosis was induced in rats by bilateral occlusion of the renal arteries. The experimental group received exogenous epidermal growth factor infused directly into the renal arterial circulation. Serum creatinine concentration was measured daily for 1 week. Epidermal growth factor receptor binding was measured by autoradiography of whole kidney sections. Renal cell proliferation was measured by incorporation of [3H]thymidine into DNA. 2. Serum creatinine concentration increased after acute tubular necrosis with a peak at 48 h and remained elevated above control levels after 7 days. Binding of radiolabelled epidermal growth factor occurred in all regions of the kidney 48 h after ischaemia. Treatment with exogenous epidermal growth factor attenuated the rise in serum creatinine by 4 days after acute tubular necrosis and after 7 days serum creatinine was lower than in animals that did not receive epidermal growth factor. Infusion of epidermal growth factor also increased renal DNA synthesis. 3. The increase in epidermal growth factor binding in the kidney after acute tubular necrosis and the attenuation of the increase in serum creatinine concentration by administration of exogenous epidermal growth factor, suggest a role for epidermal growth factor in recovery from ischaemic damage. The increase in DNA synthesis in response to epidermal growth factor indicates that its effect may be due, at least in part, to accelerated tubular cell proliferation.

scholarly journals Possible role of glutathione peroxidase-3 and organic cation transporter-2 gene expressions in mediating protective effects of curcumin on cisplatin‐induced nephrotoxicity in rats

2020 ◽  
Vol 24 (3) ◽  
pp. 211-220
Author(s):  
Abdolrahman Biabangard ◽  
◽  
Naser Khalaji ◽  
Morteza Bagheri ◽  
Bagher Pourheydar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Peroxidation ◽  
Glutathione Peroxidase ◽  
Serum Creatinine ◽  
Organic Cation ◽  
Kidney Tissue ◽  
Organic Cation Transporter ◽  
Tunel Staining ◽  
Cisplatin Nephrotoxicity

Introduction: Cisplatin induced nephrotoxicity may limit the clinical use of this drug. The aim of this study was to investigate the mechanism of the possible renoprotective effect of curcumin in cisplatin nephrotoxicity. Methods: Thirty male Wistar rats were randomly divided into five groups: 1- control (0.5ml normal saline ip, daily for 10 constitutive days); 2- cisplatin (10mg/kg ip, single dose at the first day); 3- cisplatin + curcumin (10mg/kg ip, dissolved in 5% DMSO, daily for 10 constitutive days); 4- cisplatin + vehicle (5% DMSO, 0.3ml ip) and 5- curcumin (10mg/kg ip). At the end of the study, urine and blood samples were obtained for biochemical (BUN, creatinine, sodium and potassium) analysis. The right kidneys were kept in 10% formalin for H&E and TUNEL staining, and the left kidneys were used for type 2 organic cation transporter (OCT2) and type 3 glutathione peroxidase (GPx3) gene expression and malondialdehyde measurements. Results: Cisplatin significantly increased serum creatinine, BUN, potassium and kidney lipid peroxidation. However, the effect of cisplatin on Gpx3 and OCT2 gene expression was not statistically significant. Curcumin treatment decreased serum creatinine, BUN, and kidney lipid peroxidation, but increased GPx3 and OCT2 gene expression. Moreover, curcumin significantly reversed the cisplatin-induced kidney tissue injury and decreased apoptosis. Conclusion: It is concluded that the ameliorative effect of curcumin in cisplatin nephrotoxicity was assumed to be due to antioxidant effect of this agent. The role of curcumin in mediating uptake of cisplatin is still unclear.

α-Melanocyte-simulating hormone and interleukin-10 do not protect the kidney against mercuric chloride-induced injury

2002 ◽  
Vol 282 (5) ◽  
pp. F795-F801 ◽  
Author(s):  
Takehiko Miyaji ◽  
Xuzhen Hu ◽  
Robert A. Star
Keyword(s):  
Serum Creatinine ◽  
Tissue Repair ◽  
Time Course ◽  
Interleukin 10 ◽  
Tubular Damage ◽  
Myeloperoxidase Activity ◽  
Melanocyte Stimulating Hormone ◽  
Leukocyte Accumulation ◽  
Outer Stripe ◽  
Injury Models

The anti-inflammatory cytokines α-melanocyte-stimulating hormone (MSH) and interleukin (IL)-10 inhibit acute renal failure (ARF) after ischemia or cisplatin administration; however, these agents have not been tested in a pure nephrotoxic model of ARF. Therefore, we examined the effects of α-MSH and IL-10 in HgCl2-induced ARF. Mice were injected subcutaneously with HgCl2 and then given vehicle, α-MSH, or IL-10 by intravenous injection. Animals were killed to study serum creatinine, histology, and myeloperoxidase activity. Treatment with either α-MSH or IL-10 did not alter the increase in serum creatinine, tubular damage, or leukocyte accumulation at 48 h after HgCl2 injection. Because α-MSH and IL-10 are active in other injury models that involve leukocytes, we studied the time course of tubular damage and leukocyte accumulation to investigate whether leukocytes caused the tubular damage or accumulated in response to the tubular damage. Tubular damage was present in the outer stripe 12 h after HgCl2 injection. In contrast, the number of leukocytes and renal myleoperoxidase activity were normal at 12 h but were significantly increased at 24 and 48 h after injection. We conclude that neither α-MSH nor IL-10 altered the course of HgCl2-induced renal injury. Because the tubular damage preceded leukocyte infiltration, the delayed leukocyte accumulation may play a role in the removal of necrotic tissue and/or tissue repair in HgCl2-induced ARF.

scholarly journals Cisplatin Nephrotoxicity and Protection by Milk Thistle Extract in Rats

2005 ◽  
Vol 2 (3) ◽  
pp. 383-386 ◽  
Author(s):  
Gholamreza Karimi ◽  
Mohammad Ramezani ◽  
Zahra Tahoonian
Keyword(s):  
Serum Creatinine ◽  
Protective Effect ◽  
Renal Toxicity ◽  
Methanolic Extract ◽  
Male Rats ◽  
Milk Thistle ◽  
Tubular Damage ◽  
Cisplatin Nephrotoxicity ◽  
Tubular Necrosis ◽  
Single Intraperitoneal Injection

The protective effect of methanolic extract of milk thistle seeds and silymarin against cisplatin-induced renal toxicity in male rats after a single intraperitoneal injection of 3 mg kg−1 cisplatin were studied. Over 5 days, cisplatin-treated rats showed tubular necrosis and elevation in blood urea nitrogen (BUN) and serum creatinine (Scr). Pretreatment of animals with silymarin (50 mg kg−1) or extract (0.6 g kg−1) 2 h before cisplatin prevented the tubular damage. Rats treated with silymarin or extract 2 h after cisplatin had BUN and Scr significantly lower than those receiving cisplatin, but mild to moderate necrosis was observed. These results suggested that milk thistle may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplatin to limit renal injury.

scholarly journals Protective effect of ganoderan on renal damage in rats with chronic glomerulonephritis

2008 ◽  
Vol 31 (4) ◽  
pp. 212 ◽  
Author(s):  
Wei-De Zhong ◽  
Hui-Chan He ◽  
Ru-Biao Ou ◽  
Xue-Cheng Bi ◽  
Qi-Shan Dai ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Protective Effect ◽  
Renal Damage ◽  
Light And Electron Microscopy ◽  
Kidney Tissue ◽  
Chronic Glomerulonephritis ◽  
Protective Effects ◽  
Model Group ◽  
Sprague Dawley ◽  
Urine Protein

Purpose: To investigate the protective effect of ganoderan on renal damage in rat models with chronic glomerulonephritis induced by adriamycin. Methods: 48 healthy Sprague-Dawley rats were randomly divided into three groups: control, nephritic model and ganoderan treatment groups. Changes of the following indices in the three groups were observed 6 weeks after treatment: 24-hour urine protein, albumen, serum creatinine, cholesterol. Histopathological observations of the renal cortex were made by light and electron microscopy. Results: Compared with controls, levels of 24-hour urine protein (9.60±0.57mg/d vs. 82.50±3.18mg/d), serum creatinine (35.25±2.63?mol/L vs. 44.75±8.06?mol/L) and cholesterol (1.15±0.10mmol/L vs. 4.02±0.25mmol/L) of rats in the nephritic model group were increased (P < 0.05), and the concentration of albumen was decreased (35.98±1.34g/L vs. 19.05±0.62g/L, P < 0.05). Ganoderan administration decreased 24-hour urine protein (82.50±3.18mg/d vs. 45.01±3.94mg/d, P < 0.05). Following ganoderan, the pathological changes in kidney tissue were improved compared with those in the nephritic model group. Conclusion: Ganoderan exerts protective effects in rats with chronic glomerulonephritis induced by ADR. Ganoderan reduced 24-hour urine protein, serum creatinine, cholesterol, improving renal function and reducing the severity of renal injury.

scholarly journals Characterization of Polymyxin B-Induced Nephrotoxicity: Implications for Dosing Regimen Design

2012 ◽  
Vol 56 (9) ◽  
pp. 4625-4629 ◽  
Author(s):  
Kamilia Abdelraouf ◽  
Kirk H. Braggs ◽  
Taijun Yin ◽  
Luan D. Truong ◽  
Ming Hu ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Kidney Tissue ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Renal Tissue ◽  
Total Daily Dose ◽  
Sprague Dawley ◽  
Kaplan Meier ◽  
Drug Concentrations ◽  
The Impact

ABSTRACTThe increasing prevalence of multidrug-resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the nephrotoxic properties of polymyxin B are still poorly understood. The objective of this study was to characterize nephrotoxicity associated with polymyxin B, with an emphasis on examining the impact of dosing frequencies on the onset of nephrotoxicity. Sprague-Dawley rats were divided into two groups and administered the same total daily dose of polymyxin B subcutaneously but with different dosing frequencies (either 20 mg/kg of body weight every 24 h [q24h] or 5 mg/kg q6h). Drug concentrations in renal tissue were compared between the two groups at 24 h. Kidney tissues were harvested at 48 h and compared histologically. Serum creatinine was measured daily for up to 10 days, and nephrotoxicity was defined as a significant elevation in serum creatinine (≥2× baseline). Kaplan-Meier analysis was used to compare the onset of nephrotoxicity. Polymyxin B-induced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. Extensive injury of the proximal tubules was observed. The lesions were more severe and higher drug concentrations were achieved in the kidneys of the q6h dosing group. The q24h dosing group experienced a more gradual onset of nephrotoxicity, which could be attributed to the lower kidney tissue drug concentrations (48.5 ± 17.4 μg/g versus 92.1 ± 18.1 μg/g of polymyxin B1,P= 0.04). Preferential accumulation of polymyxin B in the kidneys suggests that uptake to renal cells is a nonpassive process and q24h dosing was less nephrotoxic than q6h dosing.

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