HgCl2-induced Acute Renal Failure Research Articles

Changes in the renal function after acute mercuric chloride exposure in the rat are associated with renal vascular endothelial dysfunction and proximal tubule NHE3 inhibition

Mercury is an environmental pollutant and a threat to human health. Mercuric chloride (HgCl2)-induced acute renal failure has been described by several reports, but the mechanisms of renal dysfunction remain elusive. This study tested the hypothesis that HgCl2 directly impairs renal vascular reactivity. Additionally, due to the mercury toxicity on the proximal tubule, we investigated whether the HgCl2-induced natriuresis is accompanied by inhibition of Na+/H+ exchanger isoform-3 (NHE3). We found that 90-min HgCl2 infusion (6.5 μg/kg i.v.) remarkably increased urinary output, reduced GFR and renal blood flow, and increased vascular resistance in rats. “In vitro” experiments of HgCl2 infusion in isolated renal vascular bed demonstrated an elevation of perfusion pressure in a concentration- and time-dependent manner, associated with changes on the endothelium-dependent vasodilatation and the flow-pressure relationship. Moreover, by employing “in vivo” stationary microperfusion of the proximal tubule, we found that HgCl2 inhibits NHE3 activity and increases the phosphorylation of NHE3 at serine 552 in the renal cortex, in line with the HgCl2-induced diuresis. Changes in renal proximal tubular function induced by HgCl2 were parallel to increased urinary markers of proximal tubular injury. Besides, atomic spectrometry showed that mercury accumulated in the renal cortex. We conclude that acute HgCl2 exposure causes renal vasoconstriction that is associated with reduced endothelial vasodilator agonist- and flow-mediated responses and inhibition of NHE3-mediated sodium reabsorption. Thus, our data suggest that HgCl2-induced acute renal failure may be attributable at least in part by its direct effects on renal hemodynamics and NHE3 activity.

Rhubarb Anthraquinones Protect Rats against Mercuric Chloride (HgCl₂)-Induced Acute Renal Failure.

Mercury (Hg) causes severe nephrotoxicity in subjects with excess exposure. This work attempted to identify whether a natural medicine—rhubarb—has protective effects against mercuric chloride (HgCl2)-induced acute renal failure (ARF), and which of its components contributed most to the treatment. Total rhubarb extract (TR) were separated to the total anthraquinones (TA), the total tannins (TT) and remaining component extract (RC). Each extract was orally pre-administered to rats for five successive days followed by HgCl2 injection to induce kidney injury. Subsequently, renal histopathology and biochemical examinations were performed in vitro to evaluate the protective effects. Pharmacological studies showed that TR and TA, but not TT or RC manifested significant protection activity against HgCl2-induced ARF. There were also significant declines of serum creatine, urea nitrogen values and increases of total protein albumin levels in TR and TA treated groups compared to HgCl2 alone (p < 0.05). At last, the major components in TA extract were further identified as anthraquinones by liquid chromatography coupled mass spectroscopy. This study thus provides observational evidences that rhubarb could ameliorate HgCl2-induced ARF and its anthraquinones in particular are the effective components responsible for this activity in rhubarb extract.

Potential health‐promoting effects of astaxanthin: A high‐value carotenoid mostly from microalgae

The ketocarotenoid astaxanthin can be found in the microalgae Haematococcus pluvialis, Chlorella zofingiensis, and Chlorococcum sp., and the red yeast Phaffia rhodozyma. The microalga H. pluvialis has the highest capacity to accumulate astaxanthin up to 4-5% of cell dry weight. Astaxanthin has been attributed with extraordinary potential for protecting the organism against a wide range of diseases, and has considerable potential and promising applications in human health. Numerous studies have shown that astaxanthin has potential health-promoting effects in the prevention and treatment of various diseases, such as cancers, chronic inflammatory diseases, metabolic syndrome, diabetes, diabetic nephropathy, cardiovascular diseases, gastrointestinal diseases, liver diseases, neurodegenerative diseases, eye diseases, skin diseases, exercise-induced fatigue, male infertility, and HgCl₂-induced acute renal failure. In this article, the currently available scientific literature regarding the most significant activities of astaxanthin is reviewed.

ICAM-1 expression and leukocyte accumulation in inner stripe of outer medulla in early phase of ischemic compared to HgCl2-induced ARF

After ischemia/reperfusion (I/R), as well as after toxic insults, there is significant infiltration of leukocytes in the kidney. It is well known that antibodies against adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1)] protect the kidney against acute ischemic injury. In contrast, same antibody treatment did not protect the rat kidney against toxic acute renal failure (ARF) induced by HgCl2. Protection obtained by anti-adhesion treatment in I/R injury is an early phenomenon, since delaying the administration of anti-ICAM-1 for 8 hours did not protect the kidney anymore. The aim of this study was to compare the early ICAM-1 expression and leukocyte accumulation in different zones of ischemic and toxic injury. Male Lewis rats were injected with HgCl2 (2 mg/kg, subcutaneously) or uninephrectomized Lewis rats were submitted to 30 degrees C warm ischemia (I/R injury). Rats were sacrificed at 2, 6, 12 and 24 hours. ICAM-1 (1A29) expression in kidney was evaluated morphometrically. Different subsets of leukocytes were stained by immunohistochemistry and counted in cortex, the outer stripe of the outer medulla (OSOM) and the level of the inner stripe of the outer medulla (ISOM). Although the functional and morphologic damage was comparable between the I/R and toxic ARF group, different ICAM-1 expression could be observed early after injury. ICAM-1 expression in the ISOM started already 2 hours after the onset of I/R injury, and was increased after 12 hours in the cortex and after 24 hours in the OSOM. In contrast, during the first 24 hours after injury, ICAM-1 expression in HgCl2-injured kidneys was not different from noninjured kidneys in the ISOM and the cortex, whereas in the OSOM, ICAM-1 expression increased. The number of polymononuclear cells (PMNs) was low in noninjured kidneys and did not increase in time after both I/R injury and after HgCl2-induced ARF. In the ISOM, significant monocyte and T-cell accumulation was observed early after I/R but not after HgCl2. There was no significant T-cell accumulation in the cortex or in the OSOM. After HgCl2, almost no leukocyte accumulation and up-regulation of ICAM-1 was observed the first 12 hours after injury. In contrast, very early after I/R injury, increased expression of ICAM-1 goes along with monocyte and T-cell accumulation in the ISOM, endorsing this particular zone as critical in renal I/R injury. These observations contribute to the understanding why anti-ICAM-1 treatment in acute I/R injury is successful, but fails in acute toxic injury induced by HgCl2.

Decreased Expression of Brain Nitric Oxide Synthase in Macula Densa Cells and Glomerular Epithelial Cells of Rats with Mercury Chloride-Induced Acute Renal Failure

To elucidate the mechanisms responsible for the development of HgCl 2-induced acute renal failure (ARF), we examined the expression of brain type (b) nitric oxide synthase (NOS), which is involved in the generation of the vasodilator nitric oxide (NO), in the renal cortex of rats at 20 h after exposure to 7.5 mg/kg HgCl 2. Both blood urea nitrogen and serum creatinine were significantly increased in rats exposed to HgCl 2 relative to control rats, indicating the induction of ARF resulting from HgCl 2 exposure. Histopathological analysis demonstrated that, in addition to necrosis of proximal tubule epithelial cells, necrosis of macula densa cells and swelling of glomerular epithelial cells were observed in the renal cortex of rats with HgCl 2-induced ARF. Consequently, the number of pars maculata segments was decreased by 42% in rats with HgCl 2-induced ARF compared to control rats. The primary sites of bNOS mRNA and protein expression were macula densa cells and glomerular epithelial cells in the renal cortex of control rats and rats with HgCl 2-induced ARF. The abundance of the bNOS mRNA and protein was significantly decreased in rats with HgCl 2-induced ARF relative to control rats. These observations suggest that the production of the vasodilator NO derived from bNOS is decreased at the glomerulus level in the HgCl 2-induced ARF setting. Thus, the reduction in bNOS expression may in part contribute to the progression of HgCl 2-induced ARF through the deterioration of glomerular hemodynamics. In addition, the decrease in bNOS expression may be primarily the result of cell injury caused by the cytotoxic effect of HgCl 2.

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

The anti-inflammatory cytokines alpha-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 alpha-MSH and IL-10 in HgCl(2)-induced ARF. Mice were injected subcutaneously with HgCl(2) and then given vehicle, alpha-MSH, or IL-10 by intravenous injection. Animals were killed to study serum creatinine, histology, and myeloperoxidase activity. Treatment with either alpha-MSH or IL-10 did not alter the increase in serum creatinine, tubular damage, or leukocyte accumulation at 48 h after HgCl(2) injection. Because alpha-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 HgCl(2) 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 alpha-MSH nor IL-10 altered the course of HgCl(2)-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 HgCl(2)-induced ARF.

Melatonin attenuates acute renal failure and oxidative stress induced by mercuric chloride in rats.

We evaluated the effect of melatonin (Mel), a potent scavenger of reactive oxygen species, in the course of HgCl(2)-induced acute renal failure. Rats received by gastric gavage 1 mg/kg of Mel (n = 21) or vehicle (n = 21), 30 min before the subcutaneous injection of HgCl(2) (2.5 mg/kg). Rats were killed at 24, 48, and 72 h, and plasma creatinine (S(cr)), renal histology, proliferative activity, apoptosis, and superoxide-producing cells were studied. We also determined the renal content of malondialdehyde (MDA) and glutathione (GSH) and the activities of glutathione peroxidase and catalase. Mel pretreatment (Mel plasma levels of 3.40 +/- 3.15 microgram/ml at the time of HgCl(2) injection) prevented the increment in S(cr) and reduced tubular necrosis from 41.0 +/- 10.5 to 4.2 +/- 5.1% of proximal tubules (P < 0.01). Apoptosis and postnecrotic proliferative activity were twice more intense in the group untreated with Mel. Increment in renal content of MDA and decrease in GSH resulting from HgCl(2) toxicity were prevented by Mel. Mel also induced an important reduction in superoxide-positive cells. In contrast to the beneficial effects of pretreatment with Mel, the administration of Mel in conjunction with HgCl(2) had no effect on the oxidative damage and did not prevent nephrotoxicity. We conclude that the beneficial effects of pharmacological doses of Mel are due to its antioxidant properties.

Hemin pretreatment ameliorates aspects of the nephropathy induced by mercuric chloride in the rat

Mercuric chloride (HgCl 2) is known to be a nephrotoxicant. When HgCl 2 is administered into rats, acute renal failure (ARF) is induced. Heme oxygenase-1 (HO-1) is antioxidative enzyme and is known to play a protective role against the oxidative injury. To elucidate the cytoprotective role of HO-1 against the nephrotoxicant-induced ARF, we examined the effect of hemin, HO-1 inducer, on HgCl 2-induced ARF. Subcutaneous administration of hemin (30 mg/kg body weight) into rats once a day for two successive days obviously induced HO-1 protein in the kidneys at 24 h after the last injection. Under this situation, when HgCl 2 (1 mg/kg body weight) was intraperitoneally injected into rats at 24 h after the last injection of hemin improved the serum creatinine (SCr) and blood urea nitrogen (BUN) levels, markers for renal injury, at 24 h after the HgCl 2 injection as compared with the control rats without hemin pretreatment (HgCl 2 treatment alone). This result was further confirmed by histopathological analysis. These findings strongly suggest that the preinduction of HO-1 ameliorates the subsequent HgCl 2-induced acute renal injury.

Differential expression of renal adenosine A 1 receptors induced by acute renal failure

The distribution of renal adenosine A 1 receptors was investigated in rats with glycerol- or mercuric chloride (HgCl 2)-induced acute renal failure. Receptors were localised by autoradiography using [ 3H]8-cyclopentyl-1,3-dipropylxanthine ([ 3H]DPCPX), a selective A 1 adenosine receptor antagonist. In saline-injected control animals, significant labelling with [ 3H]DPCPX was detected in glomeruli, the inner stripe of outer medulla, and the inner medulla. Sixteen hours following induction of glycerol-induced acute renal failure (ARF), a 34% increase in labelling in glomeruli was noted compared to saline-injected controls, and by 48 hr, glomerular labelling had increased by 200%. In addition, 48 hr following glycerol injection, significant labelling was now detected in the cortical labyrinth and medullary rays whilst, in the inner medulla, labelling had decreased by 34%. By contrast to glycerol-induced ARF, the only significant change noted 48 hr following induction of HgCl 2-induced ARF was a 39% decrease in labelling in the inner medulla. It is concluded that glycerol-induced ARF results in differential expression of renal adenosine A 1 receptors with increased expression in the cortex and reduced expression in the inner medulla. Increased density of A 1 receptors in glomeruli may account, at least in part, for the increased renal vasoconstrictor response to adenosine and depressed glomerular filtration rate noted previously in this type of acute renal failure.

Role of Angiotensin II, Endothelin-1, and Nitric Oxide in HgCl2-Induced Acute Renal Failure

To elucidate the mechanisms underlying the development of HgCl2-induced acute renal failure (ARF), we examined the expression of endothelin (ET)-1, endothelial (e) nitric oxide synthase (NOS) and inducible (i) NOS, and a role of angiotensin II (ANG II) and tumor necrosis factor (TNF) in glomeruli and cortices from rats at 20 h after exposure of HgCl2. Prepro-ET-1 and iNOS mRNA were significantly increased in glomeruli and cortices from rats with HgCl2-induced ARF. However, eNOS mRNA was markedly decreased in glomeruli of rats with HgCl2-induced ARF. Blockade of the action of endogenous ANG II with TCV-116, an ANG II receptor type 1 antagonist, or prior administration of TNF antibody (Ab) neutralizing TNF bioactivity or aminoguanidine, an iNOS inhibitor, substantially suppressed the increase in the expression of prepro-ET-1 or iNOS mRNA seen in rats with HgCl2-induced ARF. Both TCV-116 and TNF Ab had no effects on the expression of eNOS mRNA. The abundance of ET-1, iNOS, and eNOS proteins was paralleled by the magnitude of each mRNA expression. Additionally, the aggravation of blood urea nitrogen and serum Cr observed in rats with HgCl2-induced ARF were significantly ameliorated together with the alleviation of proximal tubule epithelial cell injury when the expression of prepro-ET-1 or iNOS mRNA was blunted by prior administration of TCV-116 or prior injection of TNF Ab or aminoguanidine. These observations indicate that ANG II, ET-1, and NO may play an important role in the progression of HgCl2-induced ARF through the acceleration of proximal tubule epithelial cell injury and the deterioration of glomerular hemodynamics. In HgCl2-induced ARF, the gene expression of ET-1 or iNOS is at least in part up-regulated at the transcription level by endogenous ANG II or TNF.

Altered expression of endothelin-1 and endothelial nitric oxide synthase in the juxtaglomerular apparatus of rats with HgCl 2-induced acute renal failure

A progressive fall in glomerular capillary plasma flow ( Q A) is observed in mercury chloride (HgCl 2)-induced acute renal failure (ARF) although the site of the main lesion of this ARF is the proximal tubule. To elucidate this mechanism, we examined the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) protein at the glomerulus level in the kidneys of control rats and rats with HgCl 2-induced ARF. Both ET-1 and eNOS protein were detected in the juxtaglomerular cells of afferent arterioles. The expression of ET-1 was significantly increased in ARF rats when compared to control rats. Inversely, the expression of eNOS protein was markedly reduced in ARF rats as opposed to control rats. These observations suggest the participation of the vasoconstrictor, ET-1 and the vasodilator, NO in a reduction in Q A observed in HgCl 2-induced ARF.

The repetitive activation of extracellular signal-regulated kinase is required for renal regeneration in rat

In this study, we investigated the activation of p42 extracellular signal-regulated kinase (ERK2) during renal regeneration after HgCl 2-induced acute renal failure (ARF) in rat. ERK2 activation was observed at 5 and 29 hr after HgCl 2 injection, respectively. The tyrosine phosphorylation of hepatocyte growth factor receptor (c-MET) occurred between 2.5 and 5 hr after the treatment. On the other hand, the phosphorylation of epidermal growth factor receptor (EGFR) was transiently observed at 29 hr after the injection. The peak of ornithine decarboxylase activity as a marker of G 1 phase was at 10 hr, and subsequently the labeling index of proliferating cell nuclear antigen as a marker of S phase increased at 53 hr. These results indicate that the repetitive activation of ERK2 related to the phosphorylation of c-MET and EGFR is required for the renal regeneration in HgCl 2-induced ARF of rat.

Inducible nitric oxide synthase expression in mercury chloride-induced acute tubular necrosis.

To examine the mechanisms involved in the progression of mercury chloride (HgCl2)-induced acute tubular necrosis (ATN), we investigated the histopathological changes and the expression of inducible nitric oxide synthase (iNOS) mRNA and protein in renal cortices of rats at 20 hours after exposure to HgCl2. The expression of iNOS mRNA was significantly augmented in renal cortices of rats with HgCl2-induced acute renal failure (ARF). Likewise, the induction of iNOS protein was observed in damaged proximal tubule epithelial cells of rats with HgCl2-induced ARF. Pretreatment of rats with iNOS inhibitor aminoguanidine, however, suppressed the development of proximal tubule epithelial cell injury and prevented an increase in blood urea nitrogen and serum creatinine as well as resulting in a marked fall in iNOS mRNA and protein in rats with HgCl2-induced ARF. These observations indicate that the induction of iNOS may play a role in the progression of HgCl2-induced ATN through the exacerbation of proximal tubule epithelial cell damage.

HgCl2-induced acute renal failure and its pathophysiology

Mercury chloride (HgCl2) has a potent nephrotoxic effect. Most of Hg2+ existing in plasma following HgCl2 exposure forms a complex with sulfhydryl-containing ligands such as albumin and glutathione (GSH). The Hg(2+)-GSH complex is filtered in the glomeruli of the kidney and degraded into Hg(2+)-cysteine in the proximal tubules by the combined action of gamma-glutamyl transpeptidase and dipeptidase present in the epithelial cells. The degradation product is then incorporated and accumulated into the proximal tubule epithelial cells. The accumulated Hg2+ in the epithelial cells finally causes acute tubular necrosis (ATN) by its cytotoxic effect. At present, it is believed that tubular obstruction resulting from ATN triggers the onset of HgCl2-induced acute renal failure (ARF). A progressive fall in glomerular filtration rate (GFR) contributes to the progression of HgCl2-induced ARF. The fall in GFR may be caused by an increment in afferent arteriole resistance (RA) and a decrement in the ultrafiltration coefficient (Kf) due to mesangial cell contraction. These changes in RA and Kf may be attributed to the increased action of the vasoconstrictors, angiotensin II and endothelin-1 and to the decreased action of the vasodilator, nitric oxide observed at the glomerulus level of HgCl2-induced ARF. Accordingly, the imbalance between these vasoactive substances appears to play an important role in the progression of HgCl2-induced ARF due to reducing GFR. Further studies, however, remain to elucidate the mechanisms involved.

Insulin-like growth factor-1 (IGF-1) enhances recovery from HgCl2-induced acute renal failure

Several growth factors have been found to play an important role in the recovery from acute renal failure (ARF). The effect of the continuous subcutaneous infusion of human recombinant insulin-like growth factor (IGF)-1 (125 micrograms daily by osmotic minipumps) in a rat model of mercuric chloride (HgCl2)-induced ARF was examined. HgCl2 (4 mg/kg) induced ARF with a mortality that was unaffected by IGF-1. However, IGF-1 significantly enhanced functional and histologic recovery in the survivors, as measured by serum creatinine and creatinine clearance and by histologic scoring. Solution hybridization RNAase protection assays showed that renal IGF-1 mRNA, IGF-1 receptor (IGF-1R) mRNA, and IGF-binding protein-1 (IGFBP-1) mRNA were unaffected by exogenous IGF-1, but this treatment significantly increased renal IGF-1 in ARF rats compared with normal rats and ARF rats not receiving IGF-1. After ARF renal mRNA for IGF-1 was decreased, IGF-1R was unchanged and IGFBP-1 was increased. Similar changes occurred in IGF-1-infused ARF rats. Thus, (1) IGF-1 enhances recovery from nephrotoxic ARF both functionally and histologically; (2) in nephrotoxic ARF, there is (a) a reduction in IGF-1 mRNA expression that is not prevented by IGF-1 infusion, and (b) an increase in renal IGFBP-1 mRNA. This may allow a significant increase in renal IGF-1 levels in IGF-1-infused ARF rats, despite the decrease in renal IGF-1 mRNA. A local increase in renal IGFBP-1 and IGF-1 may explain the accelerated recovery from ATN in this model. It was concluded that HgCl2-induced ARF is amenable to improvement by IGF-1 infusion and that the increase in renal IGFBP-1 mRNA may be an important modulator in the recovery of the kidney.

Dynamic computed tomography (CT) in the rat kidney and application to acute renal failure models

Renal dynamic CT scanning is suitable for determining the excretion of contrast medium in the cortex and medulla of the kidney, which is valuable for understanding the pathogenesis of disease processes in various conditions. This form of scanning would be convenient for use, if a method of application to the rat kidney were available. Therefore, we developed a method of applying renal dynamic CT to rats and evaluated the cortical and medullary curves, e.g., the corticomedullary junction time which is correlated to creatinine clearance, in various rat models of acute renal failure. The rat was placed in a 10 degrees oblique position and a bilateral hilar slice was obtained before and 5, 10, 15, 20, 25, 30, 40, 50, 60, 80, 100, 120, 140, 160 and 180 sec after administering 0.5 ml of contrast medium using Somatom DR. The width of the slice was 4 mm and the scan time was 3 sec. The corticomedullary junction time in normal rats was 23.0 +/- 10.5 sec, the peak value of the cortical curve was 286.3 +/- 76.7 Hounsfield Unit (HU) and the peak value of the medullary curve was 390.1 +/- 66.2 HU. Corticomedullary junction time after exposure of the kidney was prolonged compared to that of the unexposed kidney. In rats with acute renal failure, the excretion pattern of contrast medium was similar in both the glycerol- and HgCl2-induced acute renal failure models.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunochemical Study of Epidermal Growth Factor in Rats with Mercuric Chloride-Induced Acute Renal Failure

Urine contains high concentrations of epidermal growth factor (EGF), and EGF is a potent growth promoter for proximal tubular cells. In the present study, urinary and whole-kidney EGF levels were investigated in rats with mercuric chloride (HgCl2)-induced acute renal failure (ARF) using a specific radioimmunoassay for rat EGF to clarify changes in EGF after toxic injury. Male Wistar rats were given HgCl2 (2 mg/kg, subcutaneously) or saline. Serum urea nitrogen and creatinine levels were measured for 4 days after toxin administration. Forty-eight hours after toxic injury, urinary immunoreactive EGF levels in HgCl2-treated rats decreased significantly compared with control rats (1.62 +/- 0.15 versus 3.78 +/- 0.21 ng/mg creatinine; p < 0.01). Urinary immunoreactive EGF was at its lowest level 96 h after toxic injury (0.64 +/- 0.06 ng/mg creatinine; p < 0.001). Twenty-four hours after toxic injury, renal immunoreactive EGF levels increased significantly compared with control rats (22.04 +/- 2.12 versus 4.84 +/- 0.70 ng/g wet weight tissue; p < 0.001), and the increase persisted for as long as 48 h (13.36 +/- 1.61 ng/g wet weight tissue; p < 0.05). In summary, urinary immunoreactive EGF levels decreased and renal EGF levels increased in rats with HgCl2-induced ARF. These findings suggest that there is an impairment in the excretion of EGF in rats with HgCl2-induced ARF and that local paracrine production of EGF continues in ARF.

Effect of partial nephrectomy on mercuric chloride-induced acute renal failure

We investigated the effect of partial nephrectomy on mercuric chloride (HgCl2)-induced acute renal failure (ARF) in rats. HgCl2 (2 mg/kg) was subcutaneously injected to male Wistar rats 2 days or 2 weeks after either partial nephrectomy or sham surgery. Both deterioration of renal function (serum creatinine, creatinine clearance, and fractional excretion of sodium) and renal tubular damage due to HgCl2-induced ARF were inhibited by 5/6 nephrectomy. A moderate inhibitory effect was also noted by uninephrectomy. The levels of renal tissue ATP and total nucleotide did not increase 12 and 48 hours after uninephrectomy. These results suggest that partial nephrectomy is effective in suppressing the development of HgCl2-induced ARF. The mechanisms of the protection are not explained completely by a consequence of hypertrophy or an acceleration of intracellular energy metabolism. Intrarenal blood flow redistribution may be involved in one of the mechanisms.

Epidermal growth factor accelerates renal repair in mercuric chloride nephrotoxicity

Repair and recovery of ischemic or nephrotoxic acute renal failure (ARF) are dependent upon renal tubule cell regeneration. Because epidermal growth factor (EGF) is a potent growth promoter to renal tubule cells, experiments were undertaken to assess the effects of exogenous administration of EGF during the recovery phase of HgCl2-induced ARF. Rats were administered HgCl2 (5 mg/kg sc), and [3H]thymidine incorporation into renal tissue and blood urea nitrogen (BUN) and serum creatinine concentrations were measured at various times after toxin administration. EGF (20 microgram) was administered subcutaneously 2 or 4 h after HgCl2 injection. Exogenous EGF resulted in greater levels of renal [3H]thymidine incorporation into renal proximal tubule cells compared with those observed in nontreated animals at several time points in the first 48 h after toxic injury. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that greater than 96% of labeled cells were tubular in all examined sections. This EGF-related acceleration in DNA synthesis was associated with significantly lower peak BUN and serum creatinine levels, averaging 213 +/- 23 and 6.54 +/- 0.72 (SE) mg/dl, respectively, at 3 days in EGF-treated nephrotoxic rats compared with peak levels of 359 +/- 40 and 9.92 +/- 1.67 mg/dl (P less than 0.001, n = 7-16) at 5 days in non-EGF-treated nephrotoxic rats. EGF treatment also was associated with a return to near normal BUN and serum creatinine levels approximately 4 days earlier than that observed in non-EGF-treated animals. These findings demonstrate that exogenous EGF accelerates the repair process of the kidney after a severe toxic insult.

The role of adenosine in HgCl2-induced acute renal failure in rats

It has been proposed that adenosine mediates the renal hemodynamic changes in acute renal failure (ARF) and that these changes are pathogenic in reducing glomerular filtration rate. Consistently, adenosine-receptor antagonists such as theophylline have been shown to have protective effects in several experimental models of ARF. The present experiments were designed to explore the potential role of adenosine in HgCl2-induced ARF in rats. In isolated perfused rat kidneys, HgCl2 increased adenosine production and induced a concentration-dependent vasoconstriction. However, the vasoconstriction was unrelated to adenosine production and was not antagonized by theophylline. During the initiation phase of HgCl2-induced ARF in intact rats (first 4 h after injection), theophylline failed to reverse the reduction in inulin clearance, and this failure could not be attributed to a loss of vascular responsiveness to adenosine, since N6-cyclohexyladenosine, a receptor agonist, produced a further reduction in inulin clearance. Furthermore, theophylline actually had deleterious effects during the maintenance phase of HgCl2-induced ARF in intact unanesthetized rats, as evidenced by higher mean serum creatinine values in theophylline-injected rather than in saline-injected rats, on both the second and third days after HgCl2 injection. Therefore HgCl2 acutely increases renal adenosine production, but increased adenosine does not mediate acute HgCl2-induced renal vasoconstriction, and adenosine-receptor antagonism does not have protective effects during the initiation or the maintenance phases of HgCl2-induced ARF in rats. These results provide no support for the hypothesis that increased adenosine mediates the hemodynamic changes in HgCl2-induced ARF.