Biomedical subjects

Orson W Moe

Publications and source records attributed to Orson W Moe.

48 records · Page 3Linked to original sources

PubMed2003

Iron metabolism in end stage renal failure: rationale for re-evaluation of parenteral iron therapy.

PURPOSE OF REVIEW: In this article we will examine the basis for using chronic high dose parenteral iron therapy in dialysis patients. RECENT FINDINGS: There are increasing data that dialysis patients fare better in many respects if they have higher hematocrit values although the real optimal hematocrit has not been defined. There is an increasing tendency to use parenteral iron to achieve this goal. SUMMARY: Although parenteral iron achieves seemingly favourable short results, there are no data for its safety in the long term. On the contrary, there are reasons to suggest possible iron overload with chronic use.

Anemia, Iron-Deficiency↗

PubMed2003

Albumin regulates the Na+/H+ exchanger 3 in OKP cells.

Albumin filtered by the glomerulus is reabsorbed in the proximal tubule. We have shown previously that proteinuria stimulates the proximal tubular Na(+)/H(+) exchanger 3 (NHE3) in rats. Activation of NHE3 may be a pathophysiologically important factor in the development of renal salt and water retention observed in the nephrotic syndrome. For examining whether albumin is a specific inducer of proximal tubular Na(+)/H(+) exchange and to determine the molecular mechanisms by which it regulates Na(+)/H(+) exchange, the effect of albumin on NHE3 in opossum kidney cells was studied. Albumin activated Na(+)/H(+) exchange in a time- and dose-dependent manner up to 100% in 48 h. In the early phase of stimulation (2 to 12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, increased NHE3 activity was accompanied by increase in cell surface NHE3 protein. The increase in surface NHE3 was associated with increased bidirectional trafficking of NHE3 protein between intracellular compartments and the cell surface. At 48 h, total cell NHE3 protein abundance and mRNA were increased as well. Whereas NHE3 translation was increased, NHE3 protein half-life remained unchanged. The effects of albumin on NHE3 protein abundance were modified by hydrocortisone in a complicated pattern. These results indicate that albumin directly regulates proximal tubular NHE3 at multiple levels.

Albumins↗

PubMed2002

Molecular aspects of acute inhibition of Na(+)-H(+) exchanger NHE3 by A(2)-adenosine receptor agonists.

Adenosine regulates Na(+) homeostasis by its acute effects on renal Na(+) transport. We have shown in heterologously transfected A6/C1 cells (renal cell line from Xenopus laevis) that adenosine-induced natriuresis may be effected partly via A(2) adenosine receptor-mediated inactivation of the renal brush border membrane Na(+)-H(+) exchanger NHE3. In this study we utilized A6/C1 cells stably expressing wild-type as well as mutated forms of NHE3 to assess the molecular mechanism underlying A(2)-dependent control of NHE3 function. Cell surface biotinylation combined with immunoprecipitation revealed that NHE3 is targeted exclusively to the apical domain and that the endogenous Xenopus NHE is located entirely on the basolateral side of A6/C1 transfectants. Stimulation of A(2)-adenosine receptors located on the basolateral side for 15 min with CPA (N6-cyclopentyladenosine) acutely decreased NHE3 activity (microspectrofluorimety). This effect was mimicked by 8-bromo-cAMP and entirely blocked by pharmacological inhibition of PKA (with H89) or singular substitution of two PKA target sites (serine 552 and serine 605) on NHE3. Downregulation of NHE3 activity by CPA was attributable to a reduction of NHE3 intrinsic transport activity without change in surface NHE3 protein at 15 min. At 30 min, the decrease in transport activity was associated with a decrease in apical membrane NHE3 antigen. In conclusion, two highly conserved target serine sites on NHE3 determine NHE3 modulation upon A(2)-receptor activation and NHE3 inactivation by adenosine proceeds via two phases with distinct mechanisms.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2002

Etiological role of estrogen status in renal stone formation.

PURPOSE: Estrogen may protect against kidney stone formation since nephrolithiasis is more common in men than in women. Moreover, the incidence of stones rises after menopause in women. We examined the contribution of estrogen to kidney stone risk by comparing outpatient evaluations in the 2 genders, and in estrogen treated and untreated postmenopausal women. MATERIALS AND METHODS: We reviewed the results of the initial evaluation of 1,454 adult calcium oxalate stone formers, including 1,050 men and 404 women. Of the postmenopausal women 39 and 50 were estrogen treated and untreated, respectively. Samples of urine and blood were collected 1 week after the imposition of a diet restricted moderately in sodium and calcium, and modestly in oxalate and animal protein. RESULTS: Compared with men the daily excretion of urinary calcium, oxalate and uric acid was lower in women. Women had lower saturations of calcium oxalate and brushite as well as lower excretion of undissociated uric acid. Compared with men urinary calcium was lower in women until age 50 years, when it equaled that of men. Citrate was equal in the genders until the age 60 years, when it tended to decrease in women. Compared with nontreated postmenopausal women those treated with estrogen had lower mean 24-hour calcium plus or minus SD (155 +/- 62 versus 193 +/- 90 mg. per day, p <0.02), mean 2-hour fasting urine calcium (0.08 +/- 0.05 versus 0.12 +/- 0.09 mg./mg. creatinine, p <0.01) and mean calcium oxalate saturation (5.07 +/- 2.27 versus 6.48 +/- 3.44, p <0.05). CONCLUSIONS: The lower risk of stone formation in women may be due to the lower urinary saturation of stone forming salts. Estrogen treatment may decrease the risk of stone recurrence in postmenopausal women by lowering urinary calcium and calcium oxalate saturation.

Adult↗

PubMed2002

Pathophysiology of uric acid nephrolithiasis.

Humans although a predominantly ureotylic organism, has preserved the ability to excrete nitrogen as uric acid and ammonia. An imbalance between these two secondary modes of nitrogen excretion has resulted in uric acid precipitation in human urine. Uric acid nephrolithiasis can arise from diverse etiologies all with distinct underlying defects converging to one or more of three defects of hyperuricosuria, acidic urine pH, and low urinary volume, originating from secondary, genetic or heretofore undefined (idiopathic) causes. A subset of idiopathic uric acid nephrolithiasis (gouty diathesis) may be the "tip of the icebergp" of a broader systemic illness characterized by insulin resistance. A novel renal manifestation of insulin resistance is a mild defect in ammonium excretion, which is not severe enough to disturb acid-base homeostasis, but is sufficient to set up the chemical milieu for uric acid nephrolithiasis.

Humans↗

PubMed2002

Role of c-SRC and ERK in acid-induced activation of NHE3.

BACKGROUND: In the renal proximal tubule, chronic acidosis causes increases in apical membrane NHE3 activity, which serve to increase transepithelial H+ secretion and return systemic pH to normal levels. Incubation of cultured renal epithelial cells in acid media activates c-Src. METHODS: OKP cells were incubated in control (pH 7.4) or acid (7.0) media, and NHE3 activity measured as cytoplasmic pH (pHi) recovery from an acid load using BCECF. c-Src, ERK, and JNK kinase activities were measured by immune complex kinase assays with enolase, MBP, and GST-c-Jun, respectively, as substrates in the in vitro assays. To determine the role of c-Src in acid-induced NHE3 activation, cells were transfected with vector alone or a dominant negative c-Src (c-SrcK295M). RESULTS: Expression of dominant negative c-srcK295M in OKP cells prevented acid-induced activation of NHE3. Incubation of OKP cells in acid media increased ERK activity and c-fos expression, but did not increase JNK activity. Acidosis in vivo also activated renal cortical c-Src and ERK kinases, whereas incubation of 3T3 cells in acid media activated c-Src but not ERK kinase. Expression of c-srcK295M did not affect ERK or c-fos activation by acid incubation. Inhibition of MEK with PD98059 inhibited activation of NHE3 by acid incubation. CONCLUSIONS: These studies suggest that acidosis activates c-Src and MEK/ERK/c-fos. While both pathways are necessary for activation of NHE3, they are activated independently.

Acidosis↗

PubMed2002

Pathophysiologic basis for normouricosuric uric acid nephrolithiasis.

BACKGROUND: Low urinary pH is the commonest and by far the most important factor in uric acid nephrolithiasis but the reason(s) for this defect is (are) unknown. Patients with uric acid nephrolithaisis have normal acid-base parameters according conventional clinical tests. METHODS: We studied steady-state plasma and urinary parameters of acid-base balance in subjects with normouricosuric pure uric acid stones. We also tested the ability of these subjects to excrete ammonium in response to an acute acid load. We compared these parameters in patients with pure uric acid stones to patients with mixed uric acid/calcium oxalate stones, pure calcium stones, and normal volunteers. RESULTS: Pure uric acid stone formers have a much higher incidence of either diabetes or glucose intolerance. After equilibration to a control diet, patients with uric acid stones have lower urinary pH and they excrete less of their acid as ammonium. This is compensated by higher titratable acidity and hypocitraturia. Despite their low baseline urinary pH, uric acid stone formers further acidify their urine after an acid load because of a severely impaired ammonia excretory response. Their characteristics are significantly different from normal volunteers and pure calcium stone formers. Patients with mixed uric acid/calcium stones exhibit intermediate characteristics. CONCLUSION: We propose that certain patients with normouricosuric uric acid nephrolithiasis have a renal acidification disease. The primary defect lies in renal ammonium excretion, which may be linked to the insulin-resistant state. Although net acid excretion is maintained at the expense of increased titratable acidity and to some degree hypocitraturia, the compromise is acid urine pH and may result in uric acid nephrolithiasis.

Adult↗

PubMed2002

Bicarbonate reabsorption and NHE-3 expression: abundance and activity are increased in Henle's loop of remnant rats.

BACKGROUND: The bulk of bicarbonate reabsorption along the loop of Henle (LOH) is localized at the level of the thick ascending limb (TAL) and is mainly dependent on the presence of luminal Na+-H+ exchanger (NHE-3). We investigated whether the reduction of renal mass is associated with alterations in LOH bicarbonate transport coupled to changes in NHE-3 gene expression and in vivo activity. METHODS: Sham-operated and remnant rats (4/6 nephrectomy) were studied 15 days after the surgery. To measure net bicarbonate reabsorption (JHCO3-) superficial loops were perfused by in vivo micropuncture. Perfusate was an end-like proximal solution containing 3H-methoxy-inulin. NHE-3 gene expression was quantified by competitive PCR using an internal standard of cDNA that differed from the wild-type NHE-3 by a deletion of 76 bp. Western blot experiments were performed on TAL suspension using anti-NHE-3 antibodies. RESULTS: At various LOH bicarbonate loads, JHCO3- was constantly larger in remnant rats as compared to sham-operated animals. NHE-3 mRNA abundance was estimated to be 0.339 +/- 0.031 attomoles (amol)/ng-1 total RNA in sham-operated (N = 5) and it increased to 0.465 +/- 0.023 in remnant rats (N = 5, P < 0.01). Western blot experiments showed a significant increase of NHE-3 protein abundance in TAL of remnant rats as compared to sham-operated animals. Finally, by means of a specific NHE-3 inhibitor, S-3226, in vivo microperfusion experiments demonstrated that NHE-3 in vivo activity along the LOH was substantially increased in remnant rats in addition to the non-NHE-3 bicarbonate transport. CONCLUSIONS: These data indicate that the reduction of renal mass increases mRNA, protein abundance and in vivo activity of NHE-3 along the TAL. This may explain, at least in part, the augmented transepithelial bicarbonate transport along the LOH. Such an effect will counterbalance the increased glomerular bicarbonate load, thus preventing urinary bicarbonate loss and mitigating the ensuing metabolic acidosis.

Acid-Base Equilibrium↗

PubMed2002

Collapsing glomerulopathy: a cause of noncardiogenic pulmonary edema.

Collapsing glomerulopathy is a pathologic diagnosis characterized by obliteration of glomerular capillary lumina, seen most commonly as a primary glomerular disease in young black men. A secondary form with almost identical pathologic features is described in association with human immunodeficiency virus infection. The disease is characterized by heavy proteinuria with variable renal insufficiency at the onset followed by rapid progression to end-stage renal disease with no documented effective therapy. We describe a patient who presented with systemic manifestations, including fever, acute renal failure with massive proteinuria, and noncardiogenic pulmonary edema. Renal biopsy showed classic collapsing glomerulopathy. All known causes of noncardiogenic pulmonary edema were ruled out. The pulmonary syndrome resolved, but the renal disease progressed to end-stage renal disease. We propose consideration of collapsing glomerulopathy in the differential diagnosis of any patient presenting with a multisystem disease including acute renal failure and pulmonary edema.

Acute Kidney Injury↗

PubMed2002

Phosphatonins: a new class of phosphate-regulating proteins.

PURPOSE OF REVIEW: There is an intimate relationship between phosphate and calcium homeostasis throughout the animal kingdom. One traditional assumption is that all phosphate-regulating hormones are primarily calcium-regulating hormones. Although the notion of a circulating substance dedicated to phosphate homeostasis has existed for more than a decade, it is not until recently that these hormones have been identified. The molecular characterization of these substances will prove to be critical for understanding phosphate physiology and clinical disorders of phosphate metabolism. RECENT FINDINGS: This review will focus primarily on the first two proteins recently shown to have phosphatonin properties. Using three human diseases as models and a combination of positional cloning and differential gene expression, fibroblast growth factor 23 and frizzled-related protein 4 were shown to be associated with one or more of these diseases. Although both of these substances have phosphaturic action, their biological effects are likely to extend beyond epithelial phosphate transport. SUMMARY: The phosphatonins are a growing family of substances that may act on multiple organs in autocrine, paracrine, and endocrine modes to regulate phosphate metabolism. As this list expands, the need for a more rigid definition of the term phosphatonin becomes evident. The identification and characterization of these phosphate-regulatory compounds will provide a clearer understanding of how individual phosphatonins regulate phosphate in normal and disease physiology.

Animals↗

PubMed2002

Expression of epidermal growth factor and surfactant proteins during postnatal and compensatory lung growth.

We examined whether lung growth after pneumonectomy (PNX) invokes normal signaling pathways of postnatal development. We qualitatively and quantitatively assessed the immunoexpression of epidermal growth factor (EGF), its receptor (EGFR), surfactant proteins (SP) [SP-A and -D and surfactant proproteins (proSP)-B and -C] and proliferating cell nuclear antigen (PCNA) in immature and mature dog lung. We also assayed these proteins in lungs of immature dogs 3 wk or 10 mo after they underwent right PNX compared with simultaneous matched sham controls. During maturation, alveolar cell proliferation is regionally regulated in parallel with EGF and EGFR levels and inversely correlated with SP-A and proSP-C levels. In contrast, post-PNX lung growth is not associated with EGF or EGFR upregulation but with markedly increased SP-A level and moderately increased SP-D level; proSP-B and proSP-C levels did not change. We conclude that 1) signaling of EGF axis and differential regulation of SPs persist during postnatal lung development, 2) post-PNX lung growth is not a simple recapitulation of maturational responses, and 3) SP-A and SP-D may modulate post-PNX lung growth.

Aging↗

PubMed2002

Insulin activates Na(+)/H(+) exchanger 3: biphasic response and glucocorticoid dependence.

Insulin is an important regulator of renal salt and water excretion, and hyperinsulinemia has been implicated to play a role in hypertension. One of the target proteins of insulin action in the kidney is Na(+)/H(+) exchanger 3 (NHE3), a principal Na(+) transporter responsible for salt absorption in the mammalian proximal tubule. The molecular mechanisms involved in activation of NHE3 by insulin have not been studied so far. In opossum kidney (OK) cells, insulin increased Na(+)/H(+) exchange activity in a time- and concentration-dependent manner. This effect is due to activation of NHE3 as it persisted after pharmacological inhibition of NHE1 and NHE2. In the early phase of stimulation (2-12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, enhanced NHE3 activity was accompanied by an increase in total and cell surface NHE3 protein and NHE3 mRNA abundance. All the effects of insulin on NHE3 activity, protein, and mRNA were amplified in the presence of hydrocortisone. These results suggest that insulin stimulates renal tubular NHE3 activity via a biphasic mechanism involving posttranslational factors and an increase in NHE3 gene expression and the effects are dependent on the permissive action of hydrocortisone.

Animals↗