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Biomedical subjects

H Wald

Publications and source records attributed to H Wald.

At least 19 recordsLinked to original sources
PubMed2004

The CCR5Delta32 allele is associated with reduced liver inflammation in hepatitis C virus infection.

CCR5Delta32 is a deletion mutation in the chemokine receptor CCR5. Liver inflammatory activity was found to be significantly reduced (P = 0.005) in Jewish Israeli patients infected with the hepatitis C virus (HCV) carrying the CCR5Delta32 allele. The CCR5Delta32 allele does not alter susceptibility to HCV infection; however, it may play a role in the progression and outcome of the disease.

Adult↗
PubMed2001

Late-onset downregulation of NaPi-2 in experimental Fanconi syndrome.

The pathogenesis of renal phosphate (Pi) leak in Fanconi syndrome is unknown. Disorders of apical membrane transporters, leaky apical membrane, depleted cellular Pi and ATP, and impaired sodium (Na) pumps have been proposed as underlying defects. The present study examined the role of type II Na-Pi cotransport system (NaPi-2) in experimental Fanconi syndrome in rats. Following a single injection of maleic acid (MA), 75 mg/kg body weight i.p., rats were sacrificed after 90 min, 4 h, and 24 h. Renal cortical expression of NaPi-2 mRNA was determined by Northern blotting, and brush border membrane (BBM) NaPi-2 protein by Western blotting. Increased urinary excretion of phosphate was demonstrated as soon as 90 min after MA injection, and was sustained at 4 and 24 h, NaPi-2 mRNA expression and NaPi-2 protein were not decreased after 90 min. NaPi-2 mRNA decreased after 4 h, while NaPi-2 protein decreased only at 24 h. Hence, the immediate phosphaturia in experimental Fanconi syndrome may be independent of NaPi-2 downregulation, possibly resulting from energy depletion or membrane dysfunction. The decrease in NaPi-2 mRNA expression and the subsequent NaPi-2 protein decrease may account for the second-phase phosphaturia.

Animals↗
PubMed2001

Regulation of ROMK and channel-inducing factor (CHIF) in acute renal failure due to ischemic reperfusion injury.

BACKGROUND: Acute renal failure caused by ischemia followed by reperfusion is often associated with severe hyperkalemia. The present study was undertaken to characterize the effects of renal ischemia and reperfusion on plasma potassium (K) and on the gene expression of channel-inducing factor (CHIF), a putative K channel regulator, and of ROMK, the distal nephron secretory K channel. METHODS: The following groups of rats were studied: (1) sham operated (sham); (2) after one hour of ischemia by bilateral renal artery clamping (I), and after one hour of ischemia; (3) one hour of reperfusion (I-R 1 h); (4) 24 hours of reperfusion (I-R 24 h); (5) 48 hours of reperfusion (I-R 48 h); and (6) 72 hours reperfusion (I-R 72 h). The expression of CHIF and ROMK was examined by Northern blot hybridization in renal cortex, medulla, and papilla and in the colon. The abundance of ROMK protein was determined in the renal cortex and medulla by immunoblotting. RESULTS: Maximal plasma creatinine and potassium levels after ischemia and reperfusion were 470 +/- 16 micromol/L, P < 0.0001 versus sham, and 9.65 +/- 0.33 mmol/L, P < 0.0001 versus sham, respectively. The expression of CHIF was significantly down-regulated in the medulla and papilla, with a maximal decrease of 80% at 48 to 72 hours. In contrast, a most significant increase in CHIF mRNA expression (250% of baseline) was noted in the colon after 24 to 48 hours of reperfusion. ROMK expression was reduced in the cortex and was completely abolished in the medulla at 48 to 72 hours of reperfusion. Ischemia and reperfusion injury significantly decreased ROMK protein abundance to 10% of control in the medullary fractions. CONCLUSIONS: These results suggest that down-regulation of renal CHIF and ROMK may contribute at least partly to the hyperkalemia of acute renal failure after ischemia and reperfusion, while CHIF up-regulation in the colon may act as a compensatory mechanism of maintaining K balance via increased K secretion.

Acute Kidney Injury↗
PubMed2001

Vitamin D reduces renal NaPi-2 in PTH-infused rats: complexity of vitamin D action on renal P(i) handling.

Acute administration of dihydroxycholecalciferol [1,25(OH)(2)D(3)] blunts phosphaturia and increases urinary cAMP excretion in parathyroid hormone (PTH)-infused parathyroidectomized (PTX) rats. Because chronic administration of 1,25(OH)(2)D(3) enhances the phosphaturic response to exogenous parathyroid hormone despite blunting of urinary cAMP excretion, we have examined the expression of the renal cortex type II Na-P(i) cotransporter (NaPi-2) mRNA and protein in 1) chronic PTX Sabra rats, 2) PTX rats receiving a physiological dose of 1,25(OH)-2-D(3), 3) PTX rats receiving 35 ng/h of PTH, and 4) rats receiving both PTH and 1,25(OH)(2)D(3), for 7 days via osmotic minipumps. Our results confirm that there is increased phosphaturia in the PTH+1,25(OH)(2)D(3)-infused animals despite blunting of urinary cAMP excretion, a reduced filtered load of phosphate, and lack of a phosphaturic effect by 1,25(OH)(2)D(3) alone. Both PTH and 1,25(OH)(2)D(3) significantly reduced expression of renal cortex NaPi-2 mRNA and NaPi-2 protein, and the administration of PTH together with 1,25(OH)(2)D(3) had additive effects in further decreasing NaPi-2 mRNA and NaPi-2 protein levels. Expression of two other epithelial transporters, type 1 Na-sulfate and type 1 Na-glucose cotransporters, were not different between the groups, suggesting specificity of the effects of PTH and 1,25(OH)(2)D(3) on phosphate transport. The effect of chronic administration of 1,25(OH)(2)D(3) has not been noted previously, and the cellular mechanisms and signaling processes that mediate the decrease in NaPi-2 remain to be determined.

Animals↗
PubMed2001

Evaluating the effectiveness of student assistance programs in Pennsylvania.

This article presents data from an evaluation of the Pennsylvania Student Assistance Program (SAP). Focusing on both program process and effectiveness, the evaluation was conducted to determine the overall efficacy of SAPs in Pennsylvania and, more specifically, how SAP is currently being implemented. Five data collection strategies were employed: statewide surveys of SAP team members and county administrators, focus groups, site visits, and the Pennsylvania Department of Education SAP Database. A total of 1204 individual team members from 154 school buildings completed the team member survey. Fifty-three county administrators completed the county administrator survey. Focus groups were comprised of SAP coordinators, school board personnel and community agency staff. Site visits were conducted at five schools. The findings of the evaluation indicate that SAP in Pennsylvania is being implemented as designed. Recommended is the development of benchmarks and indicators that focus on the best SAP practices and the extent to which various indicators of the effectiveness of SAP are occurring at appropriate levels.

Adolescent↗
PubMed1999

1,25-Dihydroxyvitamin D3-induced calcium efflux from calvaria is mediated by protein kinase C.

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is an important regulator of bone metabolism involved in both formation and resorption. Traditionally it was assumed that vitamin D receptors are intracellular. Recent data indicate that vitamin D may also act through a membrane receptor, specifically raising intracellular calcium and inositol 1,4,5 triphosphate. The present study was undertaken to explore further the mechanism(s) of vitamin D-induced bone resorption in cultured bone. 1,25(OH)2D3 induced a dose-dependent increase of calcium efflux from cultured bone. This increase was completely obliterated by inhibition of protein kinase C (PKC) with either staurosporine or calphostin C. In cultured rat calvariae, 1,25(OH)2D3 also induced a dose-dependent translocation of PKC from cytosol to membrane. The activation of PKC by 1, 25(OH)2D3 occurred following a 30-s incubation, peaked at 1 minute, and disappeared by 5 minutes. 1,25(OH)2D3 did not increase cAMP production in similarly cultured calvaria. These results suggest that the action of 1,25(OH)2D3 on calcium flux from cultured bone is mediated, in part, via activation of PKC.

Animals↗
PubMed1998

Evidence for interference of vitamin D with PTH/PTHrP receptor expression in opossum kidney cells.

Vitamin D counters the phosphaturic action of parathyroid hormone (PTH) in rats in vivo. The present study was undertaken to examine this interaction using monolayers of Opossum kidney (OK) cells. 32P uptake, cAMP generation, PTH/PTHrP receptor mRNA expression and intracellular Ca2+ [Ca2+]i were measured in (1) control cells, (2) cells exposed to PTH, (3) cells pretreated with 1, 25-dihydroxyvitamin D3 [1,25(OH)2D3], and (4) 1,25(OH)2D3-pretreated cells exposed to PTH. 32P uptakes were in (1) 5.00+/-0.20 (mean +/-SE), in (2) 2.30+/-0.14 (P<0.001 versus group 1), in (3) 4.80+/-0. 24 (P NS versus group 1) and in (4) 3.70+/-0.20 (P<0.001 versus group 2) nmol Pi/(mg.prot 10 mm). cAMP levels were in (1) 10+/-3, in (2) 210+/-8, in (3) 12+/-4, and in (4) 122+/-12 pmol cAMP/mg protein (P<0.001 versus group 2). PTH/PTHrP receptor mRNA expression was in relative units: (1) 100+/-0, (2) 99.5+/-6.2, (3) 68.7+/-2.6 (P<0.001 versus group 1), and (4) 34.8+/-3.3 (P<0.001 versus group 1). In groups 2 and 4 PTH induced equal transient increments in [Ca2+]i. These experiments demonstrate that the effect of vitamin D on phosphate transport is associated with a commensurate diminution in PTH/PTHrP receptor gene expression and PTH-induced cAMP formation but not with Ca2+ transients. Vitamin D per se does not affect 32P uptake or cAMP generation while it slightly decreased PTH/PTHrP receptor gene expression. These observations demonstrate that: (1) 1. 25(OH)2D3 directly antagonizes the effects of PTH on 32P uptake in OK cells, (2) this effect is mediated via inhibition of PTH-induced activation of AC/cAMP system, (3) the diminution in PTH-induced cAMP formation may stem at least in part from a decrease in the expression of PTH/PTHrP receptor mRNA.

Animals↗
PubMed1998

The ontogeny of the expression of K+ channel-like gene (CHIF) in the rat kidney papilla.

Recently, an IsK-like potassium (K+) channel corticosteroid-induced gene (CHIF) was cloned. A high-K+ diet enhances, while a low-K+ diet decreases the expression of this gene. The major expression of CHIF in the adult rat kidney is in the papilla, where it is constitutive, in contrast to its inducibility by corticosteroids and a low-salt diet in the rat colon. In order to further understand the ontogeny of K+ clearance, we studied the presence of CHIF in the kidney papilla in different stages of rat development. Total RNA from rat kidney papillae of 1- to 3-day pre-labor unborn offspring, 2- to 3-day-old newborns, 10-day-old, 6-week-old, and 43-week-old rats underwent northern hybridization for CHIF and the alpha-subunit of the Na+-K+-ATPase mRNA. Minor expression of CHIF mRNA was found in fetal and newborn rat papillae, while older rats showed an age-related increase in gene expression. The expression of the alpha-sub unit of the Na+-K+-ATPase was not age related. We conclude that CHIF is present in the rat kidney papilla and the expression is related to age. The relative deficiency of CHIF in the newborn may be one of the factors responsible for the reduced K+ clearance in is period.

Aging↗
PubMed1998

Role of down-regulated CHIF mRNA in the pathophysiology of hyperkalemia of acute tubular necrosis.

Acute tubular necrosis (ATN) is associated with hyperkalemia. We have shown that the medulla is the main site of impaired sodium (Na+)/potassium (K+) pump activity in ATN. CHIF, a gene that evokes K+ conductance in oocytes, is regulated in the colon by aldosterone and in the kidney by K+ intake. It is assumed that CHIF has a role in K+ homeostasis. To characterize the impaired K+ handling in ATN, the effect of impaired renal function on CHIF mRNA expression in the kidney and colon was studied. Three groups of rats with glycerol-induced ATN were studied: (1) control group, (2) moderate-ATN group, and (3) severe-ATN group. Serum creatinine levels in the control group were 45+/-2.1 micromol/L; in the moderate-ATN group, 224.8+/-16.9 micromol/L; and in the severe-ATN group, 376.5+/-15.9 micromol/L. In the group with severe ATN, significant hyperkalemia (P < 0.001 v control group) was noted. The expression of CHIF mRNA in relative units (percentage of control) in the moderate-ATN group, in the medulla, papilla, and colon, was 16.3%+/-5.6% (P < 0.001), 94.2%+/-9.3% (P=not significant ), and 165.9%+/-11.1% (P < 0.001); and in the severe-ATN group was 11.1%+/-6.4% (P < 0.001), 73.7%+/-4% (P < 0.001), and 310.8%+/-27.3% (P < 0.001), respectively. These results show that (1) in both moderate and severe ATN, CHIF mRNA is dramatically reduced in the medulla, (2) in severe ATN, CHIF mRNA expression decreases in the papilla, and (3) CHIF mRNA is upregulated in direct relationship to the severity of ATN and to the levels of aldosterone in the colon. These results suggest that the hyperkalemia that occurs in severe ATN stems at least in part from the downregulation of CHIF mRNA in the kidney medulla and papilla. The compensatory increase in colonic CHIF mRNA is not sufficient to maintain normal serum K+ levels.

Aldosterone↗
PubMed1998

Differential regulation of ROMK expression in kidney cortex and medulla by aldosterone and potassium.

This study explores the role of K+ and aldosterone in the regulation of mRNA of the ATP-sensitive, inwardly rectifying K+ channel, ROMK, in the rat kidney. K+ deficiency downregulated ROMK mRNA in cortex to 47.1 +/- 5.1% of control (P < 0.001) and in medulla to 56.1 +/- 3. 4% (P < 0.001). High-K+ diet slightly increased ROMK mRNA in medulla to 122 +/- 9% (P < 0.05 vs. control). Adrenalectomy (Adx) downregulated cortical ROMK mRNA to 30.7 +/- 6.8% (P < 0.001 vs. control), and increased it in medulla to 138 +/- 12.9% (P < 0.02 vs. control). In Adx rats, K+ deficiency decreased ROMK mRNA in cortex and medulla similar to intact rats. The alpha1- and beta1-Na-K-ATPase subunits were regulated in parallel to that of ROMK. In medulla, ROMK mRNA correlated with serum K+ concentration at R = 0.9406 (n = 6, P < 0.001) and alpha1-Na-K-ATPase mRNA at R = 0.9756 (n = 6, P < 0.001). ROMK2 also correlated with serum K+ concentration (R = 0.895; n = 6, P < 0.01). These results show that cortical ROMK expression is regulated by aldosterone and K+, whereas the medullary ROMK mRNA is regulated by serum K+.

Adrenalectomy↗
PubMed1998

Glycerol-induced acute renal failure attenuates subsequent HgCl2-associated nephrotoxicity: correlation of renal function and morphology.

Glycerol induced acute renal failure (ARF) is known to attenuate subsequent mercuric chloride nephrotoxicity. This protection was evaluated in rats. Glycerol induced varying degrees of renal insufficiency. After 14 days, when serum creatinine (SCr) creatinine clearance (CCr) and fractional excretion of sodium (FENa) had returned to baseline, injection of mercuric chloride caused significantly milder renal insufficiency in recovered rats than in controls (SCr 356 +/- 46 vs. 475 +/- 19 mumol/L; CCr 0.12 +/- 0.02 vs. 0.02 +/- 0.02 mL/min, p < .05; and mortality 0 vs. 45%, respectively, p < .01). A striking finding was that the degree of renal insufficiency induced by mercuric chloride correlated inversely with the degree of renal insufficiency previously induced by glycerol (r = -0.496, p < .05 for SCr and CCr), but there was no correlation with other measures of previous renal function such as urine volume, sodium excretion, or FENa. Glycerol induced ARF also attenuated the renal toxicity of mercuric chloride injected 4 days after glycerol, before full recovery of renal function. The decrements in renal function after the two insults were also inversely related (r = -0.76, p < .01). A third renal insult with a second mercuric chloride injection after three weeks was still attenuated. However, after the third insult, there was no longer an inverse or any statistical relationship with previous measurements of renal function. Histopathology revealed a good correlation between peak Scr after glycerol, and percentage of tubules undergoing re-generation 14 days later (r = 0.97, p < .01). There was an inverse correlation between Scr after mercuric chloride (administered 14 days after glycerol) and percentage of tubular regeneration seen two days later (r = -0.79, p < .05). The correlations of SCr and CCr with regeneration was greater than the correlations with tubular necrosis, suggesting that the regenerative process is involved in the protection from repeated renal insults. In conclusion, glycerol-induced ARF attenuates subsequent mercuric chloride renal insult. The attenuation correlates directly with the initial glycerol-induced damage, so that the more severe the initial renal insufficiency, the milder the renal insufficiency following subsequent mercuric chloride. This protection can be seen as early as 4 days and also 14 days after previous renal insult. The degree of renal tubular regeneration correlates well with the protection seen, and probably plays a role in acquired renal resistance to repeated insults.

Acute Kidney Injury↗
PubMed1997

Differential regulation of CHIF mRNA by potassium intake and aldosterone.

The channel-inducing factor (CHIF) is an epithelial-specific transmembrane protein, which is induced by aldosterone in distal colon (but not in kidney) and can evoke K+ conductance in Xenopus oocytes. The current study examined the possibility that CHIF participates in maintaining K+ balance by assessing its regulation during variations in K+ intake. In adrenal-intact rats, high-K+ diet stimulated, whereas K+ deficiency downregulated, CHIF mRNA both in kidney and colon. The downregulation of CHIF observed in rats fed a low-K+ diet for different periods of time closely correlated with a decrease in plasma K+ but also with changes in aldosterone levels. To differentiate between the two, modulation of CHIF has been studied in adrenalectomized rats with and without corticosteroid supplementation. These experiments have demonstrated that a low-K+ intake suppresses CHIF mRNA, irrespective of aldosterone level. On the other hand, the upregulation evoked by a high-K+ load is apparent only in adrenal-intact rats. This is despite the fact that infusing rats with aldosterone and corticosterone does not increase the expression of this mRNA in kidney. These findings may suggest a role for CHIF in preserving K+ balance.

Acidosis↗
PubMed1996

Aldosterone-induced increase in the abundance of Na+ channel subunits.

The highly selective, amilorideblockable Na+ channel is a major target to the natriferic action of the mineralocorticoid aldosterone. This rat epithelial Na+ channel (rENaC) has been recently cloned from colon and is composed of three homologous subunits denoted alpha-, beta-, and gamma-rENaC (C. M. Canessa, L. Schild, G. Buell, B. Thorens, L. Gautschi, J.-D. Horisberger, and B. C. Rossier. Nature Lond. 367: 463-467, 1994). We have tested the effects of corticosteroids on the abundance of mRNA coding for each subunit in kidney cortex and distal colon. Chronic treatment of rats with aldosterone or dexamethasone evoked in kidney cortex a small induction of alpha-rENaC and no change in beta- and gamma-rENaC. In distal colon, however, beta- and gamma-rENaC were strongly induced by either aldosterone or dexamethasone, whereas alpha-rENaC was constitutively expressed. Most of the aldosterone-induced increase in beta- and gamma-rENaC mRNA took place during 3-24 h after plasma aldosterone was elevated. A similar differential induction of rENaC subunits in kidney and colon was also evoked by a Na(+)-free diet. The effects of salt deprivation were reversed by resalinating rats with a half time of < 2 h, suggesting a high turnover rate of at least beta- and gamma-rENaC. The data are consistent with the possibility that induction of channel subunits contributes to the chronic but not the acute response to aldosterone in the colon. Such a mechanism is not likely to play a major role in cortical collecting ducts.

Aldosterone↗
PubMed1996

Aldosterone induction and epithelial distribution of CHIF.

CHIF is a recently cloned, corticosteroid-induced gene which evokes K+ channel activity in oocytes (B. Attali, H. Latter, N. Rachamim, and H. Garty. Proc. Natl. Acad. Sci. USA 92: 6092-6096, 1995). To further characterize the possible role of this gene in epithelial ion transport, we have studied its epithelial distribution and hormonal induction. Northern hybridizations indicate that the zonal distribution of CHIF mRNA in kidney is: papilla >>medulla>> cortex. High levels of CHIF were also detected in a primary culture from inner medullary collecting duct (IMCD). Perfusing rats with < 20 nM aldosterone through osmotic minipumps evoked a 22.4 +/- 1.9-fold increase in colonic CHIF. A significant increase was observed 3 h after administrating the corticosteroid, but maximal response was detected only after a 72-h incubation. This response appears to be mineralocorticoid specific; perfusing or injecting rats with maximal doses of dexamethasone did not evoke a further increase in CHIF mRNA. In contrast, high levels of CHIF are expressed in kidney papilla and IMCD primary culture, irrespective of corticosteroid treatment. Thus, like the apical Na+ channel and the H(+)-K(+)-adenosinetriphosphatase, CHIF is mineralocorticoid induced in the colon but constitutively expressed in kidney.

Aldosterone↗
PubMed1996

Parathyroid hormone-induced calcium efflux from cultured bone is mediated by protein kinase C translocation.

Activation of adenylate cyclase is believed to be the major intracellular mediator of bone resorption induced by parathyroid hormone (PTH), prostaglandins, and various bone resorbing cytokines. Studies have demonstrated a dissociation between PTH-induced bone resorption and adenosine 3',5'-cyclic monophosphate (cAMP) formation, as well as suggested a role of protein kinase C (PKC) in mediating in part the actions of PTH. We therefore investigated the relative contribution of the adenylate cyclase or PKC signal transduction pathways in mediating the PTH-induced net calcium release from cultured neonatal calvariae, an in vitro model of bone resorption. PTH (10(-11) to 10(-7) M) caused a dose-dependent increase in calcium efflux from cultured bone and activated both cAMP and PKC. To determine the role of each of these second messengers in mediating PTH-induced calcium release from bone, calvariae were preincubated with either the adenylate cyclase inhibitor SQ-22536 (10(-5) to 10(-4) M) or the PKC inhibitor staurosporine (10(-7) M) before coincubation with PTH. Compared with control, PTH caused a significant calcium efflux, whereas preincubation with SQ-22536 had no effect on basal calcium efflux and partially inhibited the calcium efflux caused by PTH. In contrast preincubation with staurosporine completely obliterated the PTH-induced calcium efflux. PTH is a potent stimulator of calcium release and activates both the cAMP and PKC signal transduction pathways in cultured bone. Inhibition of PTH-stimulated PKC activity completely abolished the PTH-induced calcium efflux from calvariae, whereas PTH-induced calcium efflux persisted despite adenylate cyclase inhibition. Thus the bone resorbing effect of PTH appears to be dependent predominantly on activation of PKC.

Animals↗
PubMed1995

Effect of myo-inositol supplementation on the development of renal pathological changes in the Cohen diabetic (type 2) rat.

A lower concentration of intracellular myo-inositol has been implicated in the development of diabetic nephropathy. This was based on short-term studies showing that early administration of aldose reductase inhibitors or myo-inositol supplementation reduces increased glomerular filtration rate and partly reduces increased urinary albumin excretion in streptozotocin diabetic rats. We studied the effect of long-term (4 months) administration of 1% myo-inositol supplement to the Cohen diabetic (type 2) rat on the development of nephropathy and renal Na(+)-K(+)-ATPase. This treatment reduced the increased renal Na(+)-K(+)-ATPase activity but had no effect on blood glucose levels, body weight, increased kidney weight, or creatinine clearance and did not prevent or reduce the development of renal glomerular pathology. There was no correlation between the level of Na(+)-K(+)-ATPase activity and the degree of nephropathy. It is possible that the renal pathological changes are due to metabolic and humoral factors resulting from hyperglycaemia, other than myo-inositol depletion. The fact that myo-inositol treatment had no effect on the development of renal pathological changes but was shown to have a beneficial effect on restoring impaired conduction velocity and on the disruption of structural elements in the nerve indicates that the effect of the biological changes ensuing from hyperglycaemia vary in different tissues depending on local conditions.

Animals↗