Tubular Ischemia Research Articles

Dysregulation of ferroptosis may participate in the mitigating effect of CoCl2 on contrast-induced nephropathy

BackgroundContrast agents can directly or indirectly induce renal tubular ischemia and hypoxic damage. Given that cobalt chloride (CoCl2) can protect renal tubules, the protective effect and potential mechanism of action of CoCl2 on contrast-induced nephropathy (CIN) warrant investigation. MethodsA CIN mouse model was established to determine the protective effect of CoCl2 on renal injury in vivo. Then, TMT-based proteomics was performed to determine the differentially expressed proteins (DEPs), following which, enrichment analyses of gene ontology and the KEGG pathway were performed. In vitro, a CIN model was constructed with renal tubular epithelial cells (HK-2) to determine the effect of CoCl2 on potential targets and the role of the key protein identified from the in vivo experiments. ResultsCoCl2 treatment decreased the levels of BUN and serum creatinine (sCr), while increasing the levels of urea and creatinine (Cr) in the urine of mice after CIN injury. Damage to the renal tubules in the CoCl2 treatment group was significantly less than in the CIN model group. We identified 79 DEPs after treating the in vivo model with CoCl2, and frequently observed ferroptosis-related GO and KEGG pathway terms. Of these, Hp (haptoglobin) was selected and found to have a strong renoprotective effect, even though its expression level in kidney tissue decreased after CoCl2 treatment. In HK-2 cells, overexpression of Hp reduced the ferroptosis caused by erastin, while knocking down Hp negated the attenuation effect of CoCl2 on HK-2 cell ferroptosis. ConclusionCoCl2 attenuated kidney damage in the CIN model, and this effect was associated with the decrease in ferroptosis mediated by Hp.

Dysregulation of ferroptosis may participate in the mitigating effect of CoCl2 on contrast-induced nephropathy

BackgroundContrast agents can directly or indirectly induce renal tubular ischemia and hypoxic damage. Given that cobalt chloride (CoCl2) can protect renal tubules, the protective effect and potential mechanism of action of CoCl2 on contrast-induced nephropathy (CIN) warrant investigation. MethodsA CIN mouse model was established to determine the protective effect of CoCl2 on renal injury in vivo. Then, TMT-based proteomics was performed to determine the differentially expressed proteins (DEPs), following which, enrichment analyses of gene ontology and the KEGG pathway were performed. In vitro, a CIN model was constructed with renal tubular epithelial cells (HK-2) to determine the effect of CoCl2 on potential targets and the role of the key protein identified from the in vivo experiments. ResultsCoCl2 treatment decreased the levels of BUN and serum creatinine (sCr), while increasing the levels of urea and creatinine (Cr) in the urine of mice after CIN injury. Damage to the renal tubules in the CoCl2 treatment group was significantly less than in the CIN model group. We identified 79 DEPs after treating the in vivo model with CoCl2, and frequently observed ferroptosis-related GO and KEGG pathway terms. Of these, Hp (haptoglobin) was selected and found to have a strong renoprotective effect, even though its expression level in kidney tissue decreased after CoCl2 treatment. In HK-2 cells, overexpression of Hp reduced the ferroptosis caused by erastin, while knocking down Hp negated the attenuation effect of CoCl2 on HK-2 cell ferroptosis. ConclusionCoCl2 attenuated kidney damage in the CIN model, and this effect was associated with the decrease in ferroptosis mediated by Hp.

Mortality and pathophysiology of acute kidney injury according to time of occurrence in acute heart failure.

AimsAcute kidney injury (AKI) during acute heart failure (AHF) is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanism appears to have prognostic relevance; however, the differentiation of true, structural AKI from hemodynamic pseudo‐AKI remains a clinical challenge.Methods and resultsThe Basics in Acute Shortness of Breath Evaluation Study (NCT01831115) prospectively enrolled adult patients presenting with AHF to the emergency department. Mortality of patients was prospectively assessed. Haemoconcentration, transglomerular pressure gradient (n = 231) and tubular injury patterns (n = 253) were evaluated to investigate pathophysiological mechanisms underlying AKI timing (existing at presentation vs. developing during in‐hospital period). Of 1643 AHF patients, 755 patients (46%) experienced an episode of AKI; 310 patients (19%; 41% of AKI patients) presented with community‐acquired AKI (CA‐AKI), 445 patients (27%; 59% of AKI patients) developed in‐hospital AKI. CA‐AKI but not in‐hospital AKI was associated with higher mortality compared with no‐AKI (adjusted hazard ratio 1.32 [95%‐CI 1.01–1.74]; P = 0.04). Independent of AKI timing, haemoconcentration was associated with a lower two‐year mortality. Transglomerular pressure gradient at presentation was significantly lower in CA‐AKI compared to in‐hospital AKI and no‐AKI (P < 0.01). Urinary NGAL ratio concentrations were significantly higher in CA‐AKI compared to in‐hospital AKI (P < 0.01) or no‐AKI (P < 0.01).ConclusionsCA‐AKI but not in‐hospital AKI is associated with increased long‐term mortality and marked by decreased transglomerular pressure gradient and tubular injury, probably reflecting prolonged tubular ischemia due to reno‐venous congestion. Adequate decongestion, as assessed by haemoconcentration, is associated with lower long‐term mortality independent of AKI timing.

Caspase-3 Is a Pivotal Regulator of Microvascular Rarefaction and Renal Fibrosis after Ischemia-Reperfusion Injury.

Background Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis.Methods We performed unilateral renal artery clamping for 30 minutes and contralateral nephrectomy in wild-type mice (C57BL/6) or caspase-3-/- mice.Results Compared with their wild-type counterparts, caspase-3-/- mice in the early stage of AKI had high urine cystatin C levels, tubular injury scores, and serum creatinine levels. Electron microscopy revealed evidence of tubular epithelial cell necrosis in caspase-3-/- mice, and immunohistochemistry showed upregulation of the necroptosis marker receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in renal cortical sections. Western blot analysis further demonstrated enhanced levels of phosphorylated RIPK3 in the kidneys of caspase-3-/- mice. In contrast, caspase-3-/- mice had less microvascular congestion and activation in the early and extension phases of AKI. In the long term (3 weeks after IRI), caspase-3-/- mice had reduced microvascular rarefaction and renal fibrosis, as well as decreased expression of α-smooth muscle actin and reduced collagen deposition within peritubular capillaries. Moreover, caspase-3-/- mice exhibited signs of reduced tubular ischemia, including lower tubular expression of hypoxia-inducible factor-1α and improved tubular injury scores.Conclusions These results establish the pivotal importance of caspase-3 in regulating microvascular endothelial cell apoptosis and renal fibrosis after IRI. These findings also demonstrate the predominant role of microvascular over tubular injury as a driver of progressive renal damage and fibrosis after IRI.

Hyperoxaluria-induced tubular ischemia: the effects of verapamil on the antioxidant capacity of the affected kidneys.

To evaluate the potential protective effects of a calcium channel blocker (Verapamil) on the oxidative stress related changes with an emphasis on the antioxidant capacity of the kidneys an experimental study in rats was performed. A total of 44 rats have been included. Hyperoxaluria was induced in Group 1 by continuous administration of ethylene glycol (EG). Animals in Group 2 received Verapamil in addition to EG. Animals in Group 3 constituted the control group. In addition to the evaluation of tissue and serum levels of three scavenging enzymes, NO, MDA and T-AOC; the presence and degree of crystal formation in renal parenchyma were evaluated in all animals after 7 and 28days. Our data demonstrated that in addition to the lower level of all three scavenging enzymes (SOD, CAT and GSH) particularly during late phase evaluation (4weeks); the total antioxidant capacity (T-AOC) of these kidneys were also higher when compared with the animals receiving EG only. Tissue and serum levels of both NO and MDA indicated the preventive effect of Verapamil on the oxidative stress induced changes. Very limited or no crystallization in the kidneys treated with verapamil during early and late phase examination was observed when compared with considerable crystal formation in Group 2 animals. Verapamil treatment may preserve the oxidant capacity of the kidneys and subsequently limit the crystal deposition induced by hyperoxaluria. Verapamil could therefore be considered in the management of kidney stone formation particularly in cases with recurrent kidney stone disease.

Fat emulsion given to very low‐birthweight infants increases urinary l‐FABP

In premature infants, many factors influence the function of renal tubules, such as asphyxia, respiratory disorders, use of high-concentration oxygen, hypotension, and drug treatment. When tubular ischemia and oxidative stress develop due to renal microcirculatory pathology, urinary L-type fatty acid-binding protein (L-FABP) level increases. Urinary L-FABP level was measured over time in very low-birthweight infants (VLBWI), and the effect of fat emulsion on L-FABP level was investigated. Thirty-one VLBWI were divided into two groups with regard to treatment with fat emulsion: the lipid group (n = 20) and the control group (n = 11). Urinary L-FABP was measured before (0-3 days of age), during (7-14 days of age), and after fat emulsion treatment (21-28 days of age) in the two groups. Median urinary L-FABP level before treatment was 459 ng/mgCr (range, 22.7-5100 ng/mgCr; mean, 1067 ± 1570 ng/mgCr) and 797 ng/mgCr (range, 69-3900 ng/mgCr; mean, 1066 ± 1188 ng/mgCr) in the lipid and control groups, respectively, showing no significant difference. Median urinary L-FABP level was 624 ng/mgCr (range, 50-2050 ng/mgCr; mean ± SD, 799 ± 655 ng/mgCr) and 273 ng/mgCr (range, 31-987 ng/mgCr; mean ± SD, 359 ± 323 ng/mgCr) at 7-14 days of age, respectively, showing that the level was significantly higher in the lipid group. At 21-28 days of age, the median level was 462 ng/mgCr (range, 49-1867 ng/mgCr; mean ± SD, 557 ± 534 ng/mgCr) and 130 ng/mgCr (range, 20-993 ng/mgCr; mean ± SD, 290 ± 329 ng/mgCr), respectively, showing that L-FABP level tended to be higher in the lipid group. Fat emulsion treatment induced a significant increase in urinary L-FABP level, suggesting that fat emulsion affected the proximal tubule in VLBWI.

Intraoperative Factors Affecting Renal Outcome After Open Repair of Suprarenal Aortic Aneurysms

The open repair of suprarenal aortic aneurysm requires supraceliac aortic cross-clamping and separate renal artery reconstruction. The aim of this study was to determine the intraoperative factors responsible for postoperative renal dysfunction. Between January 1, 2000 and May 31, 2010, 54 suprarenal aortic aneurysms were repaired at our center (mean age of the patients, 66 ± 8 years). All cases were operated through a left retroperitoneal approach without left renal vein division. Acute kidney injury was defined as a 50% increase of serum creatinine level from the preoperative baseline concentration. Perioperative variables were tested to be correlated with renal dysfunction (Spearman rank). The ischemic time was 28 ± 8 minutes for the mesentery and the right kidney and 63 ± 16 minutes for the left kidney. The total aortic clamping time was 115 ± 27 minutes. The volume of autologous transfusion was 957 ± 479 mL, allogeneic transfusion was 936 ± 473 mL, and colloids and crystalloids was 7,194 ± 2,201 mL. Two patients died. Acute kidney injury occurred in 15 patients, with complete recovery at discharge. The autologous blood transfusion volume (P = 0.009, r = 0.36) and the total aortic clamping time (P = 0.04, r = 0.30) were correlated with renal dysfunction. Postoperative renal dysfunction based on the variation in creatinine serum level was transient and requires further investigation using sensitive biomarkers for tubular ischemia.

853 Hyperoxaluria-induced tubular ischemia: The effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model

853 Hyperoxaluria-induced tubular ischemia: The effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model

E178 Hyperoxaluria induced tubular ischemia: The effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model

E178 Hyperoxaluria induced tubular ischemia: The effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model

Hyperoxaluria-induced tubular ischemia: the effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model

An experimental study in rats was performed to evaluate the presence and the degree of both tubular apoptotic changes and crystallization at cortical, medullar and papillary regions of the kidney during hyperoxaluric phase and assess the possible protective effects of vitamin E and verapamil on these pathologic changes (particularly in papillary part of the affected kidneys). A total of 32 rats have been included into the study program. Hyperoxaluria was induced by continuous administration of ethylene glycol (0.75%). In addition to hyperoxaluria induction, animals in Groups 2 and 3 did receive a calcium channel-blocking agent (verapamil) and vitamin E, respectively. Histologic alterations of the kidneys including crystal formation together with apoptotic changes were evaluated on days 1, 14 and 28, respectively. Both apoptotic changes and the presence and degree of crystallization were assessed separately in renal cortical region, medulla and particularly papillary parts of the removed kidneys. Although verapamil did well limit the degree of crystal formation and apoptosis and brought it to the same levels observed in control group animals in all parts of the kidneys during intermediate phase, addition of vitamin E was failed to show the same protective effect during both intermediate and late phase evaluations. As demonstrated in our study, the limitation of both crystal deposition and apoptotic changes might be instituted by calcium channel-blocking agents. Clinical application of such agents in the prophylaxis of stone disease might limit the formation of urinary calculi, especially in recurrent stone formers.

Arterial imaging in patients with lower extremity ischemia and diabetes mellitus

Precise, comprehensive imaging of the arterial circulation is the cornerstone of successful revascularization of the ischemic extremity in patients with diabetes mellitus. Arterial imaging is challenging in these patients because the disease is often multisegmental with a predilection for the distal tibial and peroneal arteries. Occlusive lesions and the arterial wall itself are often calcified and patients presenting with ischemic complications frequently have underlying renal insufficiency. Intra-arterial digital subtraction angiography (DSA), contrast enhanced magnetic resonance angiography (MRA), and more recently, computerized tomographic angiography (CTA) have been used as imaging modalities in lower extremity ischemia. Each has specific advantages and shortcomings in this patient population, which will be summarized and contrasted in this review. DSA is an invasive technique most often performed from a femoral arterial puncture and requires the injection of arterial contrast, which can occasionally cause allergic reactions. In patients with pre-existing renal insufficiency, contrast infusion can result in worsening renal failure; although usually self-limited, it may occasionally require hemodialysis, especially in patients with diabetes. However, DSA provides the highest degree of spatial resolution and image quality. It is also the only modality in which the diagnosis and treatment of arterial disease can be performed simultaneously. MRA is noninvasive, and when enhanced with gadolinium contrast injection provides arterial images of comparable quality to DSA and in some circumstances may uncover distal arterial targets not visualized on DSA. However, spatial resolution is inferior to DSA and erroneous interpretations due to acquisition artifacts are common. Specialized equipment and imaging techniques are necessary to minimize their occurrence in the distal lower extremity. In addition, due to the risk of inducing nephrogenic systemic fibrosis, gadolinium-enhanced MRA cannot be used in patients with renal insufficiency. CTA is noninvasive and rapidly performed, with better spatial resolution than MRA, but requires the largest volume of contrast infusion, exposes patients to high-doses of radiation, and is subject to interpretive error due to reconstruction artifacts especially in heavily calcified arteries, limiting its usefulness in many patients with diabetes. For patients in whom the planned intervention is a surgical bypass, DSA and MRA will provide high quality images of the lower extremity arterial anatomy. For patients in whom a catheter-based intervention is the likely treatment, a diagnostic DSA immediately followed by a catheter-based treatment in the same procedure is the preferred approach. In patients with pre-existing renal dysfunction, in which gadolinium-enhanced MRA is contraindicated, DSA or CTA can be performed. However, patients should have an infusion of intravenous normal saline solution or sodium bicarbonate before the procedure to reduce the incidence of contrast-induced nephropathy.

Hyperoxaluria-induced tubular ischemia: the effect of verapamil on the limitation of tissue HIF-1 alpha levels in renal parenchyma

The effect of verapamil on tubular ischemia that is demonstrated by HIF-1alpha positivity in tubular cells following hyperoxaluria was evaluated in a rabbit model. Thirty-six healthy male rabbits were randomly divided into three groups. Animals in the hyperoxaluric group were fed with 0.75% ethylene glycol. The verapamil group was fed identically to the hyperoxaluric group. Additionally, the verapamil group received verapamil orally (0.1 mg/kg). The control group received no special diet. Six animals in each group were killed on the 7th day of the experiment and the remaining six at the 28th day. Kidneys of the rabbits were examined by histopathologic and immunohistochemical analysis to detect the presence and degree of HIF-1alpha positivity. On the 7th day analysis, severe and moderate degree staining for HIF-1alpha in hyperoxaluric group were shown in four and two, respectively. In the verapamil group, however, three of six specimens showed nuclear staining (moderate in two and severe in one). Two of six specimens in the control group had minimal staining. The 28th day evaluation showed that two of the hyperoxaluric group had minimal degree nuclear staining but not in the remaining four. No staining was shown in the verapamil and control group animals. Hyperoxaluria-related ischemia formation may be responsible for subsequent alterations in renal tubules. As a protective agent, verapamil was found to limit the presence of hypoxic changes as documented by HIF-1 alpha positivity in this study. These data also support the presence ischemic insult after hyperoxaluria induction in animal model.

Peritubular Ischemia Contributes More to Tubular Damage than Proteinuria in Immune-Mediated Glomerulonephritis

Proteinuria is a key factor in the progression of tubulointerstitial injury. Recently, tubular ischemia as a result of loss of peritubular capillaries has been identified as another major contributor to disease progression, but the relative contribution of these insults on tubulointerstitial damage

Nitric oxide in acute renal failure: NOS versus NOS

This overview provides information on the pathophysiology of the inducible nitric oxide synthase/nitric oxide (iNOS/NO) system in the injury to cultured renal tubular epithelia, freshly isolated proximal tubules, and the whole organ after hypoxic or ischemic insult. The findings emphasize the role of concomitant oxidative and nitrosative stress and the role of peroxynitrite in the ensuing renal dysfunction. Scavenging peroxynitrite using seleno-organic compounds like ebselen provides renoprotection against ischemic injury. These sequelae of renal ischemia are a result of endothelial dysfunction, which is most probably responsible for the "no-reflow" phenomenon and further aggravation of tubular ischemia during the early reperfusion period. Recent studies have demonstrated that transplantation of functional endothelial cells into ischemic kidney provided a dramatic renoprotective effect. In conclusion, the intricate relations between endothelial and epithelial cells, based in part on the relations between endothelial and inducible nitric oxide synthases, are perturbed in renal ischemia primarily as a result of endothelial dysfunction precipitating epithelial injury.

HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner.

Hepatocyte growth factor (HGF) has been shown to enhance recovery from renal tubular ischemia. We investigated the possibility that HGF improves recovery by preventing ischemia-induced loss of cell adhesion. Murine inner medullary collecting duct-3 (mIMCD-3) cells subjected to 90% ATP depletion demonstrated a 55% decrease in adhesion, an effect that was completely reversed by the addition of HGF. Assays examining release of adherent cells revealed similar results with 30 min of ATP depletion causing loss of adhesion of 25% of mIMCD-3 cells and HGF completely reversing this effect. In contrast, HGF was unable to reverse the loss of adhesion of cells exposed to 99% ATP depletion. Examination of the mitogen-activated protein kinase (MAPK) signaling pathway revealed that HGF could induce extracellular signal-regulated kinase (ERK) phosphorylation in control and 90% ATP-depleted cells but not in 99% ATP-depleted cells. Inhibition of ERK activation with U0126 completely blocked the HGF-dependent reversal of ATP-depleted cell adhesion. Thus ATP-depleted cells demonstrate a marked decrease in cell adhesion that is reversible by the addition of HGF. This effect of HGF requires activation of the MAPK pathway.

Reversible idiopathic acute renal failure in children with primary nephrotic syndrome.

We describe the clinical features of four pediatric patients (20 months to 10 years of age) in whom reversible idiopathic acute renal failure (RIARF) developed during the course of primary nephrotic syndrome (PNS). All patients had severe PNS and were in relapse at the onset of RIARF. This complication of PNS was preceded by primary peritonitis in three of four patients. Renal biopsy done in the early phases of RIARF showed tubular epithelial changes similar to those observed in acute tubular ischemia. All patients required dialysis. Recovery of renal function followed fluid removal in three of four patients. The RIARF lasted from 12 days to 1 year and was followed by complete recovery of renal function in all patients. We conclude that (1) RIARF is a potential complication in children with severe PNS, (2) RIARF is associated with primary ischemic renal tubular injury, and (3) recognition of the reversibility of this complication of PNS could alter long-term plans for management of renal failure in these patients.

Reversible idiopathic acute renal failure in children with primary nephrotic syndrome

We describe the clinical features of four pediatric patients (20 months to 10 years of age) in whom reversible idiopathic acute renal failure (RIARF) developed during the course of primary nephrotic syndrome (PNS). All patients had severe PNS and were in relapse at the onset of RIARF. This complication of PNS was preceded by primary peritonitis in three of four patients. Renal biopsy done in the early phases of RIARF showed tubular epithelial changes similar to those observed in acute tubular ischemia. All patients required dialysis. Recovery of renal function followed fluid removal in three of four patients. The RIARF lasted from 12 days to 1 year and was followed by complete recovery of renal function in all patients. We conclude that (1) RIARF is a potential complication in children with severe PNS, (2) RIARF is associated with primary ischemic renal tubular injury, and (3) recognition of the reversibility of this complication of PNS could alter long-term plans for management of renal failure in these patients. (J PEDIATR 1994;125:723-7)

Role of oxygen free radical species in in vitro models of proximal tubular ischemia.

Lipid peroxidation (LP) of cell membranes by oxygen free radical species (OFRS) during reflow may be a mechanism for progressive proximal tubule injury after ischemia. We examined the relationship between tubule function and an endproduct of LP, malondialdehyde (MDA), in two in vitro models using a suspension of rat proximal tubule segments (PTS). Exposure of PTS to tert-butyl hydroperoxide (tBHP), a potent oxidant, induced dose-dependent decrements in the PTS respiration (QO2) but was associated with a progressive increase in MDA. The relationship between increasing doses of tBHP, QO2, and MDA content, as well as that between MDA and QO2 were highly correlated (r greater than or equal to 0.89, n = 6). Dithiothreitol (1 mM), a sulfhydryl reagent, prevented the tBHP-induced changes in both QO2 and LP. In the second model, 45-min O2 deprivation followed by 30 min of reoxygenation produced similar decrements in QO2 as did 0.75 mM tBHP but without a rise in MDA (n = 9). Mitochondria isolated from ischemic PTS had a 49 +/- 8.2% decrement in state III respiration (P less than 0.006, n = 4) but their MDA content was unchanged. Furthermore, allopurinol, superoxide dismutase, and catalase, agents that reduce tissue OFRS, did not attenuate ischemic tubular injury (n = 9). These results suggest that OFRS do not mediate transient O2 deprivation injury to the proximal tubule.

Impaired renal concentrating ability during resuscitation from shock.

Renal concentrating ability was tested in 20 severely injured patients who received an average of 21 blood transfusions. Timed measurements were made of urine output (UO), and the clearance of creatinine glomerular filtration rate (GFR), sodium (CNa), osmols (COsm), and free water (CH2O) during operation and were repeated at 12 and 18 hours postoperatively, and on postoperative days 2 and 4. During operation the GFR was markedly reduced (36 mL/min), while UO, CNa, and COsm were all markedly increased (8.5, 5.9, and 8.1 mL/min, respectively). The CH2O was positive (0.4 mL/min). Following operation the rate of renal excretion of water and solutes was still high: UO, 4.0 mL/min; CNa, 4.3 mL/min; and COsm, 6.0 mL/min. Five hours postoperatively the CH2O had returned to normal. By day 2 the excretion rate of water had returned closer to normal: UO, 2.1 mL/min; CNa, 2.6 mL/min; COsm, 4.0 mL/min; the CH2O was normal. Subsequent study results were normal. These data demonstrate a renal concentrating impairment during and following operation. An osmotic diuresis, transient tubular ischemia, a washout of interstitial inner medullary osmoles, or some cryptic factor may be causative.

Protection against ischemic acute renal failure by prostaglandin infusion

We have shown that intravenous infusion of epinephrine (4ug/kg/min for 6 hours) into mongrel dogs consistently produces renal hemodynamic and histopathologic characteristics of ischemic acute renal failure (ARF). This study describes renal responses that were modified by intravenous infusion of prostaglandin E (PGE 2)(10 ug/min) one hour before and during a 6 hour infusion of epinephrine (4 ug/kg/min). Two groups of animals were studied: Group I (epinephrine alone) and Group II (epinephrine + PGE 2). Urine volume, glomerular filtration rate, urinary sodium excretion rate, urine osmolality, and serum urea nitrogen were measured. Renal tissues were studied using light and electron microscopy. While urine volume or glomerular filtration rate decreased significantly in both groups, they were slightly but significantly better in Group II than Group I. Urine osmolality significantly decreased in Group I but significantly increased in Group II. Group I animals became azotemic (mean serum urea nitrogen, 27 ± 1 mg/dl), whereas Group II animals showed serum urea nitrogen at the upper limits of normal (mean 20 ± 2 mg/dl). The difference was significant (P <.01). Severe acute tubular lesions were a consistent feature in Group I. Tubular lesions were less severe and infrequent in Group II animals. While mitochondrial dark bodies (electron microscopy) characterized tubular lesions in Group I, fewer mitochondria contained dark bodies in Group II animals. These dark bodies appear to be calcium and constitute a definitive sign of ischemia. Therefore, this study indicates that PGE 2 attenuates epinephrine-induced tubular ischemia and injury and ARF which may be attributed to excessive solute excretion or to inhibition of calcium influx into tubular mitochondria.