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W Lieberthal

Publications and source records attributed to W Lieberthal.

At least 55 records · Page 3Linked to original sources
PubMed1990

Cytosolic calcium and protein kinase C reduce complement-mediated glomerular epithelial injury.

In rat membranous nephropathy, protein-uria is due to formation of the C5b-9 membrane attack complex of complement (C), and is associated with morphological evidence of glomerular epithelial cell (GEC) injury. Analogous morphological changes are induced by C5b-9 in cultured GEC. In addition, in cultured GEC C5b-9 induces Ca2+ influx, as well as Ca2+ mobilization and increased 1,2-diacylglycerol due to the activation of phospholipase C. In this study we investigated how this GEC activation pattern might influence C-mediated GEC injury. We demonstrate that the C5b-9-induced increase in cytosolic Ca2+ concentration ([Ca2+]i) did not impair ATP generation by mitochondria, suggesting that it does not contribute to cytotoxicity. Moreover, this increase in [Ca2+]i protected GEC from C-mediated cytolysis. However, a large increase in [Ca2+]i (produced by the Ca2+ ionophore A23187) impaired ATP generation and aggravated C-mediated cytotoxicity, suggesting that intact mitochondrial activity is necessary for GEC to withstand C attack. Activation of protein kinase C (PKC) by phorbol myristate acetate (PMA) also decreased C-mediated cytolysis. Conversely, C lysis was enhanced in GEC that had been pretreated for 18 hours with a high dose of PMA to deplete PKC, and following PKC inhibition with H-7. Therefore, PKC activation, possibly resulting from C5b-9-induced increase in 1,2-diacylglycerol, triggered mechanisms that protected GEC from C-mediated injury. Thus, as a consequence of C5b-9-induced phospholipase activation, the amount of C-induced GEC injury is diminished.

Adenosine Triphosphate↗
PubMed1990

Protective effect of atrial natriuretic factor and mannitol following renal ischemia.

We have examined the effect of atrial natriuretic factor (ANF) administered with and without mannitol on renal function following ischemic injury in both the isolated erythrocyte-perfused rat kidney and in the rat in vivo. ANF, administered alone after 25 min ischemia in the isolated kidney, reversed postischemic vasoconstriction but did not improve glomerular filtration rate (GFR). Mannitol alone had no effect on either renal vascular resistance or GFR. However, in isolated kidneys treated with the combination of both ANF and mannitol following reflow, GFR (0.65 +/- 0.04 ml.min-1.g-1) was markedly improved compared with GFR in the untreated ischemia group (0.20 +/- 0.04 ml.min-1.g-1) and was not different from GFR in the nonischemic controls (0.68 +/- 0.05 ml.min-1.g-1). Comparable results were obtained in studies performed in vivo. In rats subjected to 45 min ischemia, GFR (0.15 +/- 0.05 ml/min) was reduced compared with the GFR in sham-operated animals (0.95 +/- 0.07 ml/min). ANF or mannitol administered alone following ischemia and reflow did not improve GFR compared with the untreated ischemic group. However, in rats subjected to ischemia and treated with a combination of ANF and mannitol postreflow, GFR (0.69 +/- 0.10 ml/min) was 4.6-fold higher than GFR in the untreated ischemic group. Thus the combination of ANF and mannitol appear to act synergistically to improve GFR following ischemic injury.

Animals↗
PubMed1989

Renal ischemia and reperfusion impair endothelium-dependent vascular relaxation.

We studied the hemodynamic response of the isolated erythrocyte-perfused kidney to 25 min of ischemia and found that renal vascular resistance (RVR) was increased in the reflow period (16.7 +/- 1.4 mmHg.ml-1.min.g following ischemia vs. 10.2 +/- 0.8 mmHg.ml-1.min.g in control kidneys). Endothelial independent vasodilators [atrial natriuretic factor (ANF) and sodium nitroprusside] prevented the increase in RVR that occurred after ischemia. In contrast, acetylcholine and the calcium ionophore A23187, two vasodilators that act by releasing endothelium-derived relaxing factor (EDRF), had no effect on the increased RVR that occurs on reflow. Two inhibitors of EDRF, methylene blue and gossypol, increased RVR in nonischemic kidneys by 45 +/- 6 and 46 +/- 11%, respectively, an increase that was comparable to that found with ischemia alone (55 +/- 7%). The increase in RVR found with the combination of EDRF inhibition and ischemia (59 +/- 5%) was the same as that found with ischemia alone. We conclude that EDRF activity is impaired following ischemia and reperfusion. This abnormality in EDRF may be an important mechanism contributing to postischemic vasoconstriction in the renal vasculature.

Animals↗
PubMed1989

Studies of the mechanism of the vasoconstrictor activity of stroma-free hemoglobin in the isolated perfused rat kidney and rabbit heart.

We have found that DBBF-Hb and Hb Ao have significantly less vasoconstrictor activity than unmodified Hb in the rabbit heart. In striking contrast to these findings, DBBF-Hb and unmodified Hb have comparable hemodynamic effects in the isolated kidney. We have demonstrated that lipophilic contamination of fraction V BSA causes vasoconstriction in the coronary vasculature and speculate that similar contaminants may contribute to the vasoconstrictor activity of SFH solutions. Finally, we have shown that renal vasoconstriction induced by DBBF-Hb is reversed by acetylcholine as well as nitroprusside. These studies suggest that renal vasoconstriction induced by DBBF-Hb is not related to inhibition of EDRF. These studies make it clear that SFH solutions have different effects on the heart and kidney vasculature. The use of both heart and kidney models should provide important information on the mechanisms by which SFH causes vasoconstriction in these two organs.

Acetylcholine↗
PubMed1988

Effects of stroma-free hemoglobin solutions on isolated perfused rabbit hearts and isolated perfused rat kidneys.

"Stroma-free" hemoglobin solutions (SFH) cause hemodynamic alterations indicative of vasoconstriction. We studied vasoconstrictor activity in isolated rabbit hearts and rat kidneys of unmodified SFH and of SFH modified by pyridoxylation or glyoxylation, with or without glutaraldehyde cross-linking. The purity and chemical composition of the solutions, all prepared by other laboratories, were not characterized by us. In isolated hearts SFH prepared by conventional methods had potent vasoconstrictor activity. Pyridoxylation or purification by ion exchange chromatography did not alter the constrictor activity. Decreased constrictor activity was observed with human SFH cross-linked by glutaraldehyde treatment, or purified by affinity chromatography, and with bovine SFH purified by ultrafiltration and preparative HPLC. In isolated kidneys modified and unmodified SFH increased renal vascular resistance and decreased glomerular filtration rate with no morphologic evidence of tubular damage.

Animals↗
PubMed1987

Hemodynamic effects of different preparations of stroma free hemolysates in the isolated perfused rat kidney.

We have examined the effects of Stroma Free Hemolysate (SFH) solutions in the isolated perfused rat kidney. Three types of SFH, stored for 6 to 8 months at 4 degrees C, were tested: 1) unmodified, 2) glyoxalated and lightly cross linked and 3) pyridoxalated and polymerized. All three SFH solutions, added to the perfusate at a concentration of approximately 420 mg/100ml, increased renal vascular resistance (RVR) and reduced glomerular filtration rate (GFR). Unmodified, glyoxalated and lightly cross linked and pyridoxalated polymerized SFH resulted in a rise in RVR of 55%, 38% and 33% respectively and a fall in GFR of 42%, 57% and 83% respectively. In order to determine whether storage had altered the effect of SFH on renal function, one of the forms of SFH (glyoxalated and lightly cross linked) was studied only 4-6 weeks after preparation. While this preparation caused an increase in RVR of 41% it did not alter GFR; filtration fraction (FF) rose. However, after further storage of this preparation for 6-7 months, the solution resulted in a marked decrease in GFR of 47% as well as a rise in RVR of 23%. We conclude that three different SFH preparations resulted in marked vasoconstriction and reductions in GFR. These deleterious effects on renal hemodynamics were noted at a concentration of hemoglobin well below that necessary to effectively improve oxygen content. Storage of the SFH solutions may cause or contribute to their effects on renal function. SFH solutions intended for use as blood substitutes should be tested for vasoconstrictor activity.

Animals↗
PubMed1987

Interactions between ADH and prostaglandins in isolated erythrocyte-perfused rat kidney.

Interactions between antidiuretic hormone (ADH) and renal prostaglandins in the regulation of sodium reabsorption and urinary concentrating ability were studied in isolated erythrocyte-perfused rat kidneys (IEPK). In this model, hemodynamic characteristics are comparable to those found in vivo, and tubular morphology is preserved throughout the period of perfusion. [Deamino]-D-arginine vasopressin (dDAVP) markedly reduced fractional sodium excretion (FE Na) in the IEPK from 3.5 +/- 0.6 to 0.45 +/- 0.14%. After indomethacin, FE Na fell still further to 0.08 +/- 0.02%. In the absence of dDAVP indomethacin had no effect on sodium excretion; FE Na was 2.4 +/- 0.6% in control and 2.0 +/- 0.4% in indomethacin-treated groups. dDAVP increased urine osmolality in the IEPK to 741 +/- 26 mosmol/kg. When prostaglandin synthesis was blocked with indomethacin, urinary osmolality increased further to 1,180 +/- 94 mosmol/kg. In isolated kidneys perfused without erythrocytes (IPK), dDAVP decreased FENa from 14.5 +/- 1.8% to 9.6 +/- 1.2%; addition of indomethacin had no further effect. dDAVP increased urine osmolality only modestly to 350 +/- 12 mosmol/kg in the IPK and indomethacin did not increase concentrating ability further (342 +/- 7 mosmol/kg). Thus the IEPK (unlike the IPK) can excrete a markedly hypertonic urine in response to ADH. ADH also enhances tubular reabsorption of sodium in the IEPK. Prostaglandins inhibit both these actions of ADH but do not directly affect sodium excretion in the absence of the hormone.

Absorption↗
PubMed1987

Effect of erythrocytes on the function and morphology of the isolated perfused rat kidney.

We have examined the effects of erythrocytes on the function and morphology of isolated rat kidneys perfused with a physiological concentration of bovine albumin (45 g/l). (1) In kidneys perfused without red cells, renal vascular resistance (RVR) was low (4.2 +/- 0.3 mm Hg/ml/min/g), fractional sodium excretion (FeNa) was high (14.5 +/- 1.8%) and concentrating ability impaired (maximum urine osmolality 343 +/- 4 mmol/kg). The erythrocyte-free kidney also developed necrosis of the cells of the medullary thick ascending limb (mTAL). (2) Erythrocytes at a hematocrit of 4-6% did not alter RVR but prevented ischemic changes in the mTAL and reduced FeNa to 9.4 +/- 0.03%. Concentrating ability was not improved by a hematocrit of 4-6% despite the presence of a morphologically normal mTAL. (3) At a hematocrit of 40-45%, RVR was increased (to 11.2 +/- 0.4 mm Hg/ml/min/g) and FeNa was further lowered to 3.5 +/- 0.6%. Also, urinary concentrating ability was markedly improved (maximum urine osmolality 640 +/- 35 mmol/kg). (4) The isolated perfused kidney (IPK) at a hematocrit of 40-45% was able to autoregulate renal perfusate flow rate of GFR but autoregulation was incomplete. A 50% increase in perfusion pressure from 100 to 150 mm Hg increased renal perfusate flow rate and GFR 27 and 29%, respectively. Thus the IPK is not able to autoregulate as efficiently as the kidney in vivo, even in the presence of red cells at a normal hematocrit.

Animals↗
PubMed1987

A role for thromboxane in complement-mediated glomerular injury.

The membrane attack complex (MAC) of complement (C) has been shown to stimulate prostaglandin (PG) and thromboxane (Tx) synthesis in nucleated cells. Because glomerular epithelial cell injury and altered permeability in rat membranous nephropathy are mediated by the MAC, the authors examined whether MAC-induced proteinuria is linked to glomerular prostanoid synthesis. In kidneys containing non-nephritogenic, non-C-fixing gamma 2 sheep anti-Fx1A (planted antigen) that were perfused in vitro with C-fixing guinea pig anti-sheep IgG and a C source (fresh human plasma, 50% vol/vol in buffered bovine albumin), heavy proteinuria developed, reaching 4.27 +/- 1.20 mg/min/g at 100-120 minutes (n = 8). Cyclooxygenase blockade with 10(-4) M indomethacin (n = 6) inhibited urinary PGE2 excretion (569 +/- 47 to 124 +/- 18 pg/min/g, P less than 0.001) and lowered proteinuria (1.06 +/- 0.42 mg/min/g, P less than 0.001). Reduced protein excretion (0.88 +/- 0.12 mg/min/g, n = 6, P less than 0.001) also occurred with inhibition of Tx synthetase by OKY-046, 10(-4) M, a dose that was shown in separate perfusions to inhibit urinary TxB2 excretion by greater than 85%. Control kidneys, without planted antigen and perfused with anti-sheep IgG and plasma, excreted 0.30 +/- 0.05 mg protein/min/g (n = 6). Because inulin clearance was reduced by indomethacin, renal hemodynamic factors may have contributed to the reduction in proteinuria observed with this drug. However, insulin clearance was not significantly affected by OKY-046, implying that inhibition of Tx synthetase reduced proteinuria independently of changes in renal hemodynamics. Thus, proteinuria in rat membranous nephropathy is due to MAC-dependent glomerular epithelial injury and is mediated, in part, by Tx.

Animals↗
PubMed1984

Stimulation of prostaglandin production in rat glomerular epithelial cells by antidiuretic hormone.

Prostacyclin (PGI2) and prostaglandin E2 (PGE2) production by rat glomerular epithelial cells in culture were stimulated by arginine vasopressin (AVP) over a dose range of 10(-9) to 10(-6) M, but only if the cells were allowed to recover from trypsin treatment. The effect of AVP was related to its pressor activity since the antidiuretic analogue of AVP, 1-deamino-8-D-Arg-vasopressin (dDAVP) had no effect. Angiotensin II and kallidin (lysyl-bradykinin) did not affect prostaglandin production by these cells. The stimulatory effect of AVP on arachidonate metabolism was inhibited by the calcium channel antagonist, nifedipine, in a dose-dependent fashion suggesting that cellular uptake of calcium was required.

Angiotensin II↗
PubMed1983

Effects of alterations in sodium and water metabolism on urinary excretion of active and inactive kallikrein in man.

Renal kallikrein is present in human urine in both an active and an inactive form. Several previous studies have examined the response of active kallikrein excretion to alterations in sodium and water metabolism, but the response of inactive kallikrein has not been evaluated systematically. We have developed a method for determining inactive kallikrein in urine using two assays. Active kallikrein is measured using a kininogenase assay. Total (active plus inactive) kallikrein is measured using a direct RIA. Inactive kallikrein is calculated from the difference between active and total kallikrein excretion. We have used this technique to study the effect of alterations in sodium and water metabolism on kallikrein excretion. Acute volume expansion with saline and moderate acute or chronic increases in water intake did not alter the excretion of either active or inactive kallikrein. Dietary sodium restriction increased the excretion of total kallikrein by 30%; active kallikrein increased 82%, while inactive kallikrein excretion was found to be unchanged. Spironolactone reduced total kallikrein excretion in subjects on a low salt diet. Again, the change in excretion was entirely attributable to the active form of the enzyme. Total kallikrein excretion increased during the first 3 days of fludrocortisone administration in subjects on a high salt intake and then plateaued. Active kallikrein increased progressively throughout the 7-day study period. Inactive kallikrein increased during the first 4 days, then fell to control levels. Thus, mineralocorticoid initially stimulates the formation and/or release into urine of both active and inactive kallikrein. Later, reciprocal changes in active and inactive enzymes occur.

Body Water↗
PubMed1982

The effect of cations on the activity of human urinary kallikrein.

We studied the effect of ions on the ability of purified human urinary kallikrein to cleave its natural substrate (kininogen) as well as two synthetic substrates, tosylarginine [3H]methyl ester and Pro-Phe-Arg-[3H]benzylamide. The kininogenase activity of kallikrein is markedly dependent upon the concentration of cations in vitro. Kininogenase activity is very low when measured in a low electrolyte buffer. The addition of cations to the reaction mixture increases activity by up to 27-fold. Maximum activity is achieved with 100 mM sodium, 100 mM potassium, or 20 mM magnesium. The activity is stable at higher concentrations of cation. Renal kallikrein is believed to act within distal tubular fluid in vivo. The concentration of cations in this fluid varies widely in response to alterations in salt and water metabolism. Thus, the relationship of kininogenase activity to the concentration of cations demonstrated in vitro may be relevant to the activity of kallikrein at its presumed site of action in the kidney. In separate experiments, we evaluated the effect of ions on the amidase and esterase activities of kallikrein which are the basis of several assays in routine use for physiological studies. In contrast to their stimulatory effect on kininogenase activity, cations inhibit amidase and to a lesser extent esterase activity. Additional studies indicate that urinary cations probably account entirely for the well known ability of normal urine to inhibit the amidase and esterase activities of kallikrein.

Anions↗
PubMed1979

Rapid recurrence of membranous nephropathy in a related allograft.

A patient with membranous nephropathy (MN) received a renal allograft from his brother. The allograft functioned immediately but nephrotic range proteinuria developed seven days after transplantation in the absence of any signs of rejection. Renal function deteriorated five weeks after transplantation due to ureteric obstruction. Nephrostomy drainage resulted in the return of renal function to normal and demonstrated that the allograft was the source of the nephrotic range proteinuria. An open renal biopsy of the allograft performed at the same time revealed the presence of recurrent MN. The recipient was investigated in an attempt to identify possible humoral immune mechanisms that may explain this very rapid recurrence of MN.

Adult↗
PubMedDate not supplied

Role of apoptosis of renal tubular cells in acute renal failure: therapeutic implications.

Acute renal failure (ARF) can be defined as a sudden loss of renal function and is a common and serious clinical problem. There are many causes of ARF but the most common cause results from injury to the renal tubular epithelial cells (RTECs). RTECs can be injured by schemia or by cytotoxic agents and, once injured, can die by necrosis or apotosis. In general, necrosis occurs in response to any severe injury, which leads to the biochemical collapse of the cell. Milder forms of the same types of injury cause apoptosis. At the cellular level there are fundamental differences between necrosis and apoptosis. Necrosis results from the additive effect of a number of independent biochemical events that are activated by severe depletion of cell energy stores. By contrast, apoptosis occurs via a coordinated, predictable and pre-determined pathway. These biochemical differences between apoptosis and necrosis have important therapeutic implications. Once a cell has been severely injured, necrosis is difficult to prevent. By contrast, the apoptotic pathway can potentially be modulated to maintain cell viability. The components of the apoptotic pathway that are potentially amenable to therapeutic modulation are discussed in detail in this review.

Acute Kidney Injury↗
PubMedDate not supplied

Vasopressin stimulates urinary kallikrein excretion in the isolated erythrocyte-perfused rat kidney.

We have found that arginine vasopressin (AVP) (10 pg/ml) stimulates urinary kallikrein in the isolated erythrocyte perfused rat kidney. (In this model, perfusate flow rate approximates blood flow rates in vivo and morphology is normal.) Urinary kallikrein excretion rose from 6.9 +/- 0.8 to 14.9 +/- 2.4 ng/min 20 min after the addition of AVP to the perfusate, and then fell towards baseline levels over the next 30 min. 1-Desamino-8-D-AVP (8 pg/ml) caused a comparable increase in kallikrein excretion. Prostaglandin synthesis inhibition with indomethacin did not alter the stimulatory effect of AVP on kallikrein excretion. Parathyroid hormone 1-34 (144 ng/ml) and calcitonin (102 ng/ml) also increased urinary kallikrein. Kallikrein excretion rose from 9.1 +/- 2.0 to 24 +/- 4.5 ng/min in response to calcitonin and from 8.3 +/- 1.6 to 43.7 +/- 3.4 ng/min following the addition of parathyroid hormone to the perfusate. Kallikrein was found to accumulate in the perfusate in a linear fashion. Based on the slope of the relationship between perfusate kallikrein and time, the rate of release of kallikrein into the perfusate was estimated to be 0.79 ng/min in control kidneys. The rate of release of kallikrein into the perfusate in kidneys treated with AVP was the same (0.74 ng/min). Thus while kallikrein is released into the perfusate, this process is not influenced by AVP. In conclusion, AVP stimulates release of kallikrein into the urine (but not the perfusate) independently of systemic events. The effect of AVP is not mediated by prostaglandins. This effect of AVP is mediated via stimulation of the V2 receptor and also occurs in response to two other hormones (calcitonin and parathyroid hormone) that are known to stimulate adenyl cyclase in the rat distal nephron.

Animals↗