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W Lieberthal

Publications and source records attributed to W Lieberthal.

At least 37 records · Page 2Linked to original sources
PubMed1997

Lysophosphatidic acid: a novel growth and survival factor for renal proximal tubular cells.

Lysophosphatidic acid (LPA) is the smallest and structurally simplest of all glycerophospholipids. LPA is a normal constituent of serum and binds with high affinity to albumin while retaining its biological activity. The effects of LPA are pleiotropic and range from mitogenesis to stress fiber formation. In this report, we demonstrate two novel functions for LPA. LPA acts as a survival factor to inhibit apoptosis of primary cultures of mouse renal proximal tubular (MPT) cells. LPA also acts as a potent mitogen for MPT cells. The ability of LPA to act as both a survival factor and a mitogen is mediated by the lipid kinase phosphatidylinositol 3-kinase (PI3K), since these activities were completely blocked by wortmannin or LY-294002, two structurally dissimilar inhibitors of PI3K. The identification of LPA as a proliferative and anti-apoptotic factor suggests a potential role for this lipid mediator during the injury and/or recovery phases following tubular damage.

Animals↗
PubMed1997

Beta1 integrin-mediated adhesion between renal tubular cells after anoxic injury.

beta 1 integrin-mediated adhesion between renal tubular cells after anoxic injury. This study examined the effect of sublethal injury, induced by ATP depletion (5 mM cyanide in the absence of dextrose), on the distribution and function of beta 1 integrins in primary cultures of mouse proximal tubular (MPT) cells. It was shown in this study that sublethal injury results in loss of focal contacts present in uninjured MPT cells, and that the beta 1 integrin molecule becomes redistributed to the apical membrane domain of sublethally injured cells. Polystyrene beads coated with Arg-Gly-Asp (RGD)-containing peptide adhere to the surface of sublethally injured MPT cells but not to control, dextrose-treated cells, indicating that the beta 1 integrins present on the apical surface of the cell remain functional. The presence of an excess of free RGD-containing peptide reduces binding of RGD-coated beads to sublethally injured MPT cells by approximately 50%. It was also demonstrated that adherence of MPT cells in suspension to cyanide-treated monolayers is increased more than 300% above adhesion to control, uninjured monolayers. This abnormal cell-cell adhesion is ameliorated by the presence of an excess of RGD-containing peptide and is reversed if cyanide-treated cells are allowed to recover for 1 h. It was concluded that the beta 1 integrin becomes expressed on the apical surface of MPT cells after sublethal injury. These apically expressed integrins remain functional and mediate aberrant adhesion between MPT cells.

Animals↗
PubMed1996

Anti-phospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a beta 2-glycoprotein I-dependent manner.

Anti-phospholipid autoantibodies (aPL) are associated with a clinical syndrome of hypercoagulability, thrombocytopenia, and fetal loss. Several groups have shown that the in vitro target of many aPL is not a pure phospholipid Ag, but is either a complex between anionic phospholipid and the plasma protein beta2-glycoprotein I (beta 2GPI) or the protein beta 2GPI alone. Anionic phospholipids are normally absent from the extracellular surface of cell membranes but redistribute from the inner to the outer leaflet during apoptosis. We show that aPL bind specifically to apoptotic, but not viable, thymocytes, and that binding is dependent upon the presence of beta 2GPI. Moreover, we show that beta 2GPI binds selectively to the surface of apoptotic thymocytes to generate an epitope for antiphospholipid autoantibodies. These findings suggest that apoptotic cells may be the natural immunogen and/or target for aPL. Moreover, we propose that the interaction of circulating beta 2GPI with redistributed anionic phospholipid may itself generate a novel ligand by which apoptotic cells are recognized directly for phagocytic clearance.

Adsorption↗
PubMed1996

Lipid peroxidation contributes to hydrogen peroxide induced cytotoxicity in renal epithelial cells.

We have examined the role of lipid peroxidation in the cytotoxicity of H2O2 in OK cells containing markedly differing amounts of cell membrane polyunsaturated fatty acids (PUFA). In OK cells grown in a serum free medium, PUFA were undetectable. The membranes of these cells contained predominantly oleic, stearic and palmitic acids. When cultured in medium containing 10% calf serum, OK cells contained measurable amounts of PUFA [linoleic (5 +/- 1%) and arachidonic acids (8 +/- 1%)]. When the serum containing medium was supplemented with 60 mM linoleic acid, the membrane content of both linoleic (21 +/- 1%) as well as arachidonic acid (15 +/- 1%) as substantially increased. The severity of injury induced by H2O2 in OK cells was substantially altered by the PUFA content of the cell membrane. Exposure of OK cells to 1.25 mM H2O2 for one hour resulted in more cell death (determined by a trypan blue assay) in cells grown in serum supplemented with linoleic acid with "normal" PUFA content (90 +/- 2%) than in cells with "reduced" levels of PUFA grown in unsupplemented calf serum (81 +/- 3%). Cells gown in defined, serum free medium with undetectable levels of PUFA suffered the least H2O2-induced lethal cell injury (47 +/- 8%). Comparable differences in the cytotoxicity of H2O2 among cells with differing PUFA content were found using a clonogenic assay of cell viability. Malondialdehyde (MDA) accumulation induced by 1.25 mM H2O2 was greater in cells with "normal" PUFA content (702 +/- 103 pM/microgram cell DNA/hr) than in cells with "reduced" PUFA (328 +/- 112 pM/100 microgram DNA/hr) and was undetectable in cells grown in defined, serum free medium. In summary, the content of PUFA of cells in culture is profoundly influenced by culture conditions. Our data provide novel and direct evidence that peroxidation of cell membranes contributes directly to the severity of cell injury and death induced by H2O2.

Animals↗
PubMed1996

Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis.

We have examined the mechanisms of cell death induced by cisplatin in primary cultures of mouse proximal tubular cells. High concentrations of cisplatin (800 microM) led to necrotic cell death over a few hours. Much lower concentrations of cisplatin (8 microM) led to apoptosis, which caused loss of the cell monolayer over several days. Necrosis was characterized by a cytosolic swelling and early loss of plasma membrane integrity. In contrast, early features of cells undergoing apoptosis included cell shrinkage and loss of attachment to the monolayers. Nuclear chromatin became condensed and fragmented in apoptosing cells. These features were absent in necrotic cells. DNA electrophoresis of cells exposed to 800 microM cisplatin yielded a "smear" pattern, due to random DNA degradation. In contrast, the DNA of apoptosing cells demonstrated a "ladder" pattern resulting from internucleosomal DNA cleavage. Antioxidants delayed cisplatin-induced apoptosis but not necrosis. Thus the mechanism of cell death induced by cisplatin is concentration dependent. Reactive oxygen species play a role in mediating apoptosis but not necrosis induced by cisplatin.

Animals↗
PubMed1996

Mechanisms of apoptosis and its potential role in renal tubular epithelial cell injury.

Cells can die by two distinct pathways: apoptosis or necrosis. Necrosis is associated with rapid metabolic collapse that leads to cell swelling, early loss of plasma membrane integrity, and ultimate cell rupture. Cytosolic contents leak from the necrotic cell causing injury and inflammation to surrounding tissue. In contrast, apoptosis is an energy-requiring, gene-directed process, which, when activated, results in cell "suicide." The morphological and biochemical characteristics of cells dying by apoptosis differ markedly from those of cells dying by necrosis. During apoptosis, cells decrease in size and round up. The nuclear chromatin undergoes condensation and fragmentation. The apoptotic cell then breaks apart into many plasma membrane-bound vesicles called "apoptotic bodies," which contain fragments of condensed chromatin and morphologically intact organelles such as mitochondria. Apoptotic cells and bodies are rapidly phagocytosed, thereby protecting surrounding tissues from injury. The rapid and efficient clearance of apoptotic cells makes apoptosis extremely difficult to detect in tissue sections. Recent studies show that multiple cytotoxic stimuli well known to cause necrosis can lead to apoptosis instead when cells are exposed to the same noxious agents at lower concentrations. This insight has led to an interest in the role of apoptosis in the pathogenesis of renal diseases that result primarily from injury to renal tubular epithelial cells. These diseases include acute and chronic renal failure from exposure of the kidney to ischemia or to cytotoxic agents. In this review we discuss some relevant aspects of the differences between necrotic and apoptotic cell death. We also present evidence to support the hypothesis that apoptosis is an important pathogenic mechanism in those forms of acute and chronic renal failure in which the renal tubular epithelial cell is the primary target of ischemic or toxic injury.

Animals↗
PubMed1996

Effects of nitric oxide inhibition on systemic and renal hemodynamics in the hemorrhaged rat.

The systemic and renal hemodynamic responses to nitric oxide (NO) inhibition with L-Name were compared in both normotensive, normovolemic rats and in rats following acute hemorrhagic hypotension. The mean arterial blood pressure increased in normovolemic as well as in hemorrhaged, hypotensive rats. The systemic vascular resistance also increased in both groups, but the increase was greater in normotensive rats (104 +/- 11%) than in hypotensive rats (64 +/- 14%). The renal vascular resistance also increased more in normotensive rats (189 +/- 20%) than in hypotensive rats (102 +/- 19%; p < 0.05). The glomerular filtration rate was markedly reduced by L-Name in normovolemic rats (from 3.0 +/- 0.1 to 2.1 +/- 0.1 ml/min/300 g), but increased in hemorrhaged rats following L-Name (from 1.8 +/- 0.2 to 2.5 +/- 0.2 ml/min/300 g). In summary, the L-Name-induced increase in vascular resistance is markedly reduced following hemorrhage, suggesting that NO production or availability is reduced. However, the NO production continues in the hemorrhaged rat and contributes substantially to the hypotension and functional renal insufficiency associated with acute severe volume depletion.

Animals↗
PubMed1995

Endothelin receptor A blockade alters hemodynamic response to nitric oxide inhibition in rats.

We examined the extent to which the systemic and renal vasoconstriction induced by nitric oxide (NO) inhibition in vivo is mediated by endothelin (ET). We examined the effects of BQ-610, a specific ETA-receptor antagonist, after NO inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) in the anesthetized rat. Mean arterial pressure (MAP) increased after L-NAME infusion from 107 +/- 2 to 133 +/- 3 mmHg (P < 0.05 vs. baseline period) then fell to 115 +/- 3 mmHg after administration of BQ-610 (P < 0.05 vs. L-NAME and baseline periods). Systemic vascular resistance (SVR) increased from 1.26 +/- 0.06 to 2.17 +/- 0.18 mmHg.ml-1.min.300 g after L-NAME (P < 0.05 vs. baseline period) then fell to 1.69 +/- 0.12 mmHg.ml-1.min.300 g after BQ-610 (P < 0.05 vs. L-NAME and baseline periods). The increase in renal vascular resistance (RVR) from 6.4 +/- 0.4 to 13.7 +/- 1.4 mmHg.ml-1.min.300 g induced by L-NAME (P < 0.05 vs. baseline period) was reduced to 11.1 +/- 1.0 mmHg.ml-1.min.300 g by BQ-610 (P < 0.05 vs. L-NAME and baseline periods). The extent to which BQ-610 reversed the L-NAME-induced increases in RVR and SVR was comparable (RVR by 40 +/- 9%; SVR by 52 +/- 7%). Glomerular filtration rate and renal blood flow were both reduced by L-NAME, but neither value increased after BQ-610, possibly because the renal vasodilation induced by ETA blockade was offset by the concomitant reduction in MAP and renal perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Functional and cytoskeletal changes induced by sublethal injury in proximal tubular epithelial cells.

Mouse proximal tubular (MPT) cells in culture were subjected to ATP depletion by incubating them with cyanide in the absence of dextrose for 1 h. This insult resulted in marked alterations in the actin cytoskeleton. These changes were not associated with a decrease in cell viability and thus reflected sublethal injury. The effect of sublethal injury on the functional integrity of the intercellular tight junction (TJ) was then examined in MPT cell monolayers grown on permeable supports. During chemical anoxia, monolayer permeability to the paracellular marker mannitol progressively increased to 297 +/- 62% of baseline after 1 h. Chemical anoxia also caused a reversible loss in cell-substrate adhesion when MPT cells were studied as confluent monolayers or as single cells. Thus disruption of the actin cytoskeleton in nonlethally injured cells results in important reversible alterations in renal epithelial function characterized by impairment of the "gate" function of the TJ as well as impaired cell-substrate adhesion. We hypothesize that sublethal epithelial cell injury without accompanying necrosis may contribute to the decrement in renal function characteristic of ischemic renal injury.

Actins↗
PubMed1994

Stroma-free hemoglobin increases blood pressure and GFR in the hypotensive rat: role of nitric oxide.

The short-term systemic and renal hemodynamic effects of two stroma-free hemoglobin (SFH) solutions, one unmodified and the other modified by cross-linking, were examined in anesthetized rats after hemorrhagic hypotension. Both forms of SFH increased mean arterial pressure (MAP) and glomerular filtration rate (GFR) to baseline (prehemorrhage) values. The increase in MAP induced by unmodified SFH was greater than the increase in MAP caused by an albumin solution isoncotic to the unmodified SFH solution. Similarly, the increase in MAP caused by the modified SFH was also substantially greater than that induced by an albumin solution of comparable oncotic pressure to the modified SFH solution. Both unmodified and modified SFH increased GFR. As with MAP, the increase in GFR induced by both SFH solutions was greater than that associated with the oncotically matched albumin solutions. In separate experiments, the effects of nitric oxide (NO) inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) on MAP after hemorrhagic hypotension and subsequent infusion of unmodified SFH or albumin were also examined. In the albumin-infused rats, L-NAME increased MAP. In marked contrast, NO inhibition with L-NAME had no further effect on MAP when infused after SFH. We conclude that both unmodified and modified SFH solutions acutely improve MAP and GFR by the combined effects of intravascular volume expansion resulting from the colloid effect of the protein and by inactivation of NO.

Animals↗
PubMed1993

Clinical relevance of the natriuretic peptides in edematous states.

The natriuretic peptide system, which comprises at least four related proteins: atrial natriuretic peptide; brain natriuretic peptide; C-type natriuretic peptide; and urodilatin, exerts important influences on central and renal hemodynamics and renal sodium excretion. Recent studies have examined the role of these peptides in the pathophysiology of edema formation in congestive heart failure, cirrhosis, and nephrotic syndrome and have explored the therapeutic value of manipulating their metabolic pathways. One striking feature appears common to all three states ie, a blunted response to the natriuretic effect of atrial natriuretic peptide, which becomes particularly severe in the late stages of each disease. However, whereas in congestive heart failure and cirrhosis the main mechanism responsible is enhanced proximal tubular reabsorption of sodium resulting in reduced distal sodium delivery to the major site of atrial natriuretic peptide action, in nephrotic syndrome a biochemical defect in the cellular response to atrial natriuretic peptide within the kidney is a more likely explanation. Most information regarding the efficacy of therapies that alter the metabolism or the local action of atrial natriuretic peptide pertain to congestive heart failure. However, continued investigation in this area may ultimately lead to interventions that play a valuable role in the future management of all three edematous states.

Atrial Natriuretic Factor↗
PubMed1993

Integrin receptors in renal tubular epithelium: new insights into pathophysiology of acute renal failure.

This review summarizes the existing evidence implicating disordered adhesion of renal tubular epithelial cells to the basement membrane in the pathophysiology of acute renal failure. The following three major lines of investigation are discussed: 1) exfoliation of renal tubular epithelial cells as a potential mechanism of tubular obstruction, 2) normal distribution of integrin receptors along the tubular apparatus, and 3) redistribution of integrin receptors and remodeling of the cytoskeleton following acute injury to renal tubular epithelium. We advance the hypothesis that the loss of the basolateral expression of integrin receptors is responsible for the exfoliation of viable proximal epithelial cells and that the redistribution of integrin receptors from the basolateral to the apical surface of epithelial cells facilitates adhesion of detached cells to the in situ cells. These two processes culminate in tubular obstruction.

Acute Kidney Injury↗
PubMed1993

Renal mouse proximal tubular cells are more susceptible than MDCK cells to chemical anoxia.

To elucidate the mechanisms responsible for the resistance of continuous cell lines to anoxic injury, we have compared the effects of ATP depletion induced by chemical anoxia on primary cultures of mouse proximal tubular (MPT) cells and on Madin-Darby canine kidney (MDCK) cells. Inhibition of ATP production by cyanide and 2-deoxyglucose (CN+DOG) in the absence of dextrose reduced cell ATP content to < 5% of control values in MPT cells and caused progressive deterioration in mitochondrial function as well as loss of cell viability in these cells. Cell free fatty acid (FFA) content rose from 4.3 +/- 0.9 to 23.7 +/- 2.0 micrograms/mg of total lipid weight after 4 h of CN + DOG (P < 0.05). The mitochondrial injury and cell death induced by CN + DOG in MPT cells was ameliorated by the addition of fatty acid-free bovine albumin to the cell medium, which reduced cell FFA content during chemical anoxia from 25.0 +/- 3.0 to 10.4 +/- 2.0 micrograms/mg (P < 0.05). The phospholipase A2 (PLA2) inhibitor, mepacrine, also resulted in functional protection and reduction of cell FFA content from 20.2 +/- 2.3 to 15.9 +/- 1.7 micrograms/mg (P < 0.05). These data suggest a role for phospholipase activation and accumulation of toxic lipid metabolites in the pathophysiology of MPT cell injury. We then compared cell injury induced by CN + DOG in MPT and MDCK cells. Despite comparable reduction in cell ATP content in the two cell types, injury was far more severe in MPT than MDCK cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1992

Role of thromboxane in mediating the intrarenal vasoconstriction induced by unmodified stroma free hemoglobin in the isolated perfused rat kidney.

Unmodified stroma free hemoglobin (SFH) increased renal vascular resistance (RVR) from 4.0 +/- 0.2 to 6.9 +/- 0.9 mmHg/ml/min in control isolated kidneys. In kidneys obtained from rats pretreated with the thromboxane synthetase inhibitor OKY-046 RVR increased from 3.9 +/- 0.3 to 4.8 +/- 0.4 mmHg/ml/min. The percent increase in RVR was greater in response to SFH in control kidneys (67 +/- 14%) than in OKY-046 treated kidneys (23 +/- 7%)(p less than 0.05). SFH resulted in a fall in glomerular filtration rate (GFR) from 0.75 +/- 0.09 to 0.21 +/- 0.04 ml/min in control kidneys while in kidneys from OKY-046 treated rats GFR fell from 0.65 +/- 0.04 to 0.54 +/- 0.06 ml/min. The percent fall in GFR was greater in vehicle treated kidneys (69 +/- 8%) as opposed to OKY-046 treated kidneys (19 +/- 7%)(p less than 0.05). The rate of urinary thromboxane excretion measured before the addition of SFH to the perfusate was 52 pg/min in the control group and 7 pg/min in the OKY-046 treated group(p less than 0.05).

Animals↗
PubMed1991

19-nor-DOC biosynthesis in the isolated perfused rat kidney.

19-nor-deoxycorticosterone (19-nor-DOC) is a potent salt retaining and hypertensinogenic mineralocorticoid that is excreted in the urine. While the precursor of 19-nor-DOC, 19-oxo-DOC, is produced by the adrenal cortex, conversion to 19-nor-DOC does not occur in the adrenal gland. We have examined the hypothesis that 19-nor-DOC is synthesized from precursors in the kidney. 19-oxo-DOC was added to the perfusate of isolated rat kidney preparations (n = 5) at a concentration of 10 microM. During 1 h of perfusion following addition of 19-oxo-DOC, 71 +/- 6% of the precursor was converted to 19-oic-DOC, an immediate precursor of 19-nor-DOC, and 8.3 +/- 1.8% was converted to 19-nor-DOC. This represents the first definitive evidence that 19-nor-DOC is produced in the kidney from adrenal precursors.

Animals↗
PubMed1991

Nitric oxide inhibition in rats improves blood pressure and renal function during hypovolemic shock.

We have examined the systemic and renal hemodynamic effects of nitric oxide (NO) inhibition with NG-monomethyl-L-arginine (L-NMMA) in normotensive rats as well as in rats with hypovolemic shock induced by hemorrhage. L-NMMA increased mean arterial blood pressure (MAP) from 114 +/- 4 to 130 +/- 6 mmHg (P less than 0.05) in the nonhemorrhaged rats and from 61 +/- 3 to 89 +/- 3 mmHg (P less than 0.05) in the hypovolemic animals. The absolute increase in MAP was greater in the hypovolemic (31 +/- 3 mmHg) than in the nonhemorrhaged (15 +/- 2 mmHg) rats (P less than 0.05). An excess of L-arginine reversed the increase in MAP induced by L-NMMA in both groups. In the normotensive rats the increase in blood pressure was associated with an elevation in renal vascular resistance (RVR; from 6.5 +/- 0.7 to 8.2 +/- 0.9 mmHg.ml-1.min-1, P less than 0.05) so that renal plasma flow (RPF) and glomerular filtration rate (GFR) were unchanged. In contrast, in the hypotensive rats, the marked increase in MAP induced by L-NMMA infusion was not associated with a significant increase in RVR. As a result L-NMMA increased both RPF (from 6.0 +/- 0.4 to 7.8 +/- 0.4 ml/min, P less than 0.05) as well as GFR (from 1.7 +/- 0.2 to 2.5 +/- 0.2 ml/min, P less than 0.05). We conclude that NO is produced and modulates peripheral resistance in normotensive rats as well as in rats with hypovolemic shock. In the hypovolemic rats NO inhibition substantially improves RPF and GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗