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W E Mitch

Publications and source records attributed to W E Mitch.

At least 73 records · Page 4Linked to original sources
PubMed1996

Protein degradation and increased mRNAs encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3H1 myocytes require an interaction between glucocorticoids and acidification.

In rats and humans, metabolic acidosis stimulates protein degradation and glucocorticoids have been implicated in this response. To evaluate the importance of glucocorticoids in stimulating proteolysis, we measured protein degradation in BC3H1 myocytes cultured in 12% serum. Acidification accelerated protein degradation but dexamethasone did not augment this response. To reduce the influence of glucocorticoids and other hormones and cytokines in 12% serum that could mediate proteolysis, we studied BC3H1 myocytes maintained in only 1% serum. Acidification of the medium or addition of dexamethasone at pH 7.4 did not significantly increase protein degradation, while acidification plus dexamethasone accelerated proteolysis. The steroid receptor antagonist RU 486 prevented this proteolytic response. Acidification of the medium with 1% serum did increase the mRNAs for ubiquitin and the C2 proteasome subunit, but when dexamethasone was added the mRNAs were increased significantly more. The steroid-receptor antagonist RU 486 suppressed this response to the addition of dexamethasone but the mRNAs remained at the levels measured in cells at pH 7.1 alone. Thus, acidification alone can increase the mRNAs of the ubiquitin-proteasome proteolytic pathway, but both acidosis and glucocorticoids are required to stimulate protein degradation. Since these changes occur without adding cytokines or other hormones, we conclude that the proteolytic response to acidification requires glucocorticoids.

Amino Acid Sequence↗
PubMed1996

Rapidly reversible acute renal failure from ureteral obstruction in pregnancy.

We report a case of acute renal failure due to bilateral ureteral obstruction that rapidly resolved after delivery. Acute renal failure secondary to bilateral ureteral obstruction is rare; to our knowledge, only 18 cases have been reported in the English literature. Review of these cases reveals that twin pregnancies, polyhydramnios, and obstruction of the solitary kidney seem to increase the risk of obstructive renal failure. Measures including induced delivery, amniocentesis, and insertion of ureteral stents or nephrostomy tubes undertaken to relieve the ureteral obstruction usually lead to rapid improvement in urine flow and renal function. Acute renal failure secondary to bilateral ureteral obstruction is a rare but reversible complication of pregnancy.

Acute Kidney Injury↗
PubMed1996

Early detection and the course of glomerular injury in patients with sickle cell anemia.

We performed a cross sectional analysis of glomerular function in 34 adult patients with sickle cell anemia (SSA). Patients were divided according to GFR and albumin excretion rate (AER): SSA controls (normal GFR and AER, N = 10), albuminuria (increased AER, but normal GFR, N = 7) and chronic renal failure (CRF, low GFR, N = 17). GFR did not correlate with age (that is, duration of disease), but was inversely related to AER and IgG excretion rates (r = -0.61 and -0.69, respectively, P < 0.001) and directly related to the hematocrit (r = 0.56, P < 0.001). Renal plasma flow was disproportionately higher than GFR, so that filtration fraction was low in all groups. Albuminuria was accompanied, even in patients with normal GFR, by a reduction in ultrafiltration coefficient (16 +/- 3 in albuminuria vs. 25 +/- 3 in controls, P < 0.05). A more severe loss of ultrafiltration coefficient and glomerular permselectivity occurred in CRF. We conclude that renal failure in SSA occurs because of glomerular injury with loss of ultrafiltration coefficient and glomerular permselectivity. The earliest clinically detectable abnormality is an increase in albumin and IgG excretion. When albuminuria is present, the ultrafiltration coefficient is already diminished even if GFR is preserved. Detection of albuminuria can identify established glomerular injury in SSA.

Adult↗
PubMed1996

Glucocorticoids and acidosis stimulate protein and amino acid catabolism in vivo.

We have shown that chronic metabolic acidosis in awake rats accelerates whole body protein turnover using stochastic modeling and a continuous infusion of L-[1-13C] leucine. To delineate the role that glucocorticoids play in mediating these catabolic responses, we measured protein turnover in awake, chronically catheterized, adrenalectomized rats in the presence or absence of glucocorticoids and/or a NH4Cl feeding regimen which induced chronic metabolic acidosis. In adrenalectomized rats receiving no glucocorticoids there was no statistical difference in amino acid oxidation, protein degradation or synthesis whether or not the rats had acidosis. In contrast, chronically acidotic, adrenalectomized rats receiving glucocorticoids demonstrated accelerated whole body protein turnover with a 84% increase in amino acid oxidation and a 26% increase in protein degradation, compared to rats not receiving glucocorticoids or those given the same dose of glucocorticoids but without acidosis. We conclude that metabolic acidosis accelerates amino acid oxidation and protein degradation in vivo, and that glucocorticoids are necessary but not sufficient to mediate the catabolic effects of metabolic acidosis.

Acidosis↗
PubMed1996

Mechanisms causing loss of muscle in acute uremia.

The mortality of acute renal failure (ARF) remains high because most illnesses associated with ARF also cause loss of muscle mass. The mechanisms causing loss of muscle mass are inhibition of protein synthesis and/or acceleration of protein degradation. Identifying which of these abnormalities is present requires understanding the principles of amino acid and protein turnover. There is evidence that ARF by itself impairs protein synthesis and stimulates protein degradation. The mechanisms causing these defects include abnormal metabolic responses to hormones and stimulation of the ATP--ubiquitin--proteasome-dependent pathway. Understanding these mechanisms could lead to rational therapies.

Acute Kidney Injury↗
PubMed1996

Metabolic acidosis stimulates protein metabolism in uremia.

It is well established that chronic renal failure is associated with loss of lean body mass. Possible explanations for protein losses include a limited ability to reduce essential amino acid oxidation and protein degradation when dietary protein is low. Alternatively, uremia could directly stimulate protein catabolism. In rats, we have uncovered evidence that metabolic acidosis not only blunts the responses to a low-protein diet but also stimulates the degradation of muscle protein. We find that the ATP-ubiquitin-proteasome-dependent pathway causing muscle protein degradation is activated by acidosis. Glucocorticoids are required but are not sufficient to elicit this catabolic response.

Acidosis↗
PubMed1996

Influence of acid loading, extracellular pH and uremia on intracellular pH in muscle.

UNLABELLED: Our previous work has shown that chronic metabolic acidosis can induce changes in protein and amino acid metabolism in muscle. The relationship of these metabolic responses to changes in muscle pH is unknown. To examine the role that acute acidosis might have on intracellular pH in rats, we evaluated the influence an acute infusion of HCl had on intracellular pH using 31P-NMR. Male rats fed 22% protein and weighing between 150 and 170 g were infused with 150 mM HCl (4 mmol/kg) over a 2- or 4-hour period. Baseline blood pH was 7.36 and dropped to 7.04 at the end of the infusion. Despite this, no changes in intracellular pH were seen. In contrast, we found that chronic acid loading (4 mmol NH4Cl/100 g/day for 5 days) produces a small change in muscle pH (0.05 pH units, p < 0.05). Chronic uremia did not change resting muscle pH despite a decrease in extracellular pH to 7.23 even though metabolic changes are well documented. CONCLUSIONS: (1) An acute acid load does not alter intracellular pH while chronic metabolic acidosis does reduce intracellular pH. (2) The lack of an acute change in intracellular pH suggests that intracellular buffering capacity changes over time.

Acidosis↗
PubMed1996

Metabolic acidosis as a uremic toxin.

Patients with chronic renal failure suffer from a muscle wasting syndrome that is characterized by loss of lean body mass and negative nitrogen balance. Evidence is provided indicating that metabolic acidosis plays a major role in initiating these adverse effects. In particular, we discuss findings suggesting that metabolic acidosis mitigates its effects by activating the cytosolic ubiquitin proteasome proteolytic pathway. Additional evidence that metabolic acidosis alters vitamin D and parathyroid hormone levels is provided. Therapy that includes correction of the metabolic acidosis with alkali in the form of sodium bicarbonate supplements has significant therapeutic implications for uremic patients with even mild degrees of metabolic acidosis.

Acidosis↗
PubMed1995

Mechanisms causing muscle loss in chronic renal failure.

The loss of lean body mass in uremia is associated with excessive morbidity and mortality. A potential mechanism causing protein catabolism is that uremia overcomes critical metabolic responses required to maintain protein balance whenever dietary protein is limited. These responses include reduced oxidation of essential amino acids, which improves the efficiency of protein utilization and a reduction in protein degradation. We find that metabolic acidosis stimulates both amino acid oxidation and protein degradation in muscle and thus could overcome the adaptive responses. The molecular mechanisms stimulating catabolism involve glucocorticoids and includes increased mRNAs of components of catabolic pathways. Studies in patients have confirmed that acidosis causes catabolism in chronic renal failure. Thus, we recommend that patients with metabolic acidosis receive an adequate diet and sufficient alkali to correct acidosis.

Acidosis↗
PubMed1995

Renal amino acid transport in adults with oxidative phosphorylation diseases.

The clinical manifestations of mitochondrial DNA (mtDNA) mutations depend on a variety of factors including ratios of normal to abnormal mtDNA and tissue-specific differences in ATP production by oxidative phosphorylation (OXPHOS). In order to investigate the effects of OXPHOS defects on renal tubule function, we characterized sodium-coupled transport processes in six individuals with OXPHOS diseases. Pathogenic mtDNA mutations were identified in five of these individuals. Sodium coupled transport processes were evaluated by determining fractional excretions of amino acids, glucose, lactate, urate, and phosphate in patients and controls. Four of the six individuals had high fractional excretions of neutral amino acids, indicating abnormal renal tubule reabsorbtion of these amino acids. Abnormalities in fractional excretions of lactate, glucose, urate, and phosphate were less pronounced. These results demonstrate that sodium-coupled transport processes in the kidney are sensitive to OXPHOS impairment. When abnormalities in these processes are encountered, an OXPHOS disease should be included in the differential diagnosis.

Adenosine Triphosphate↗
PubMed1995

Progression of overt nephropathy in non-insulin-dependent diabetes.

The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.

Adolescent↗
PubMed1995

Low-protein diets in the treatment of chronic renal failure.

Dietary protein restriction is an established method of preventing the symptoms of uremia but three questions should be asked before beginning this type of therapy: Will the diet maintain adequate nutrition? Can compliance be monitored? Will the low-protein diet prevent uremic symptoms and change the course of the disease? There are positive answers to these questions. Recently it has been shown that the metabolic acidosis associated with kidney failure causes catabolism by increasing the degradation of muscle protein and of essential amino acids. The mechanism for these responses includes increased mRNAs encoding enzymes involved in catabolic pathways. Activation of these pathways would impair the ability of patients to respond to a low-protein diet because the ability to reduce the oxidation of essential amino acids and degradation of protein would be limited.

Acidosis↗
PubMed1995

Uremic acidosis and protein metabolism.

Mechanisms causing loss of lean body mass in uremia include an inability to activate metabolic adaptations to a low-protein diet caused by anorexia, or other factors. The adaptations include decreased degradation of essential amino acids and protein. Metabolic acidosis activates specific pathways which increase catabolism by mechanisms that include stimulation of genes. The inability to adapt to dietary protein restriction causes loss of lean body mass.

Acidosis↗
PubMed1995

Rat muscle branched-chain ketoacid dehydrogenase activity and mRNAs increase with extracellular acidemia.

The rate-limiting enzyme in branched-chain amino acid catabolism is branched-chain ketoacid dehydrogenase (BCKAD). In rats fed NH4Cl to induce acidemia, we find increased basal BCKAD activity as well as maximal activity in skeletal muscle. Concurrently, there is a > 10-fold increase in mRNAs of BCKAD subunits in skeletal muscle plus an increase in cardiac muscle but not in liver or kidney. There was no increase in mRNA for malate dehydrogenase or for cytosolic glyceraldehyde-3-phosphate dehydrogenase. Evaluation of the translation capacity of BCKAD mRNAs in muscle of acidemic rats yielded more immunoreactive BCKAD whether the proteins were synthesized from muscle RNA using rabbit reticulocyte lysate or directly using postmitochondrial homogenates. Although the RNA from muscle of acidemic rats yielded twice as much BCKAD protein, we found no net increase in mitochondrial BCKAD protein in muscle by Western blotting. Because there is increased proteolysis in muscle of rats with acidemia, the increase in mRNA might be a mechanism to augment BCKAD synthesis and activity in muscle.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

Experimental acidemia and muscle cell pH in chronic acidosis and renal failure.

To test whether muscle intracellular pH (pHi) decreases when extracellular pH falls, 31P-nuclear magnetic resonance was utilized in rats made acidotic by infusion of HCl, gavage-feeding NH4Cl, or induction of chronic renal failure (CRF). A 2- or 4-h HCl infusion did not lower muscle pHi, even though serum bicarbonate fell to 5 mM. With chronic acidemia, blood pH was 7.15 +/- 0.01 vs. 7.38 +/- 0.02 in pair-fed controls, and muscle pHi was 7.09 +/- 0.01 and 7.14 +/- 0.02, respectively (P < 0.01). pHi in muscle of CRF rats (7.16 +/- 0.01) did not differ from sham-operated, pair-fed controls (7.19 +/- 0.01) despite a blood pH of 7.23 +/- 0.05 in CRF vs. 7.39 +/- 0.01 in controls. Because ion transport is abnormal in CRF, we examined whether recovery of pHi is impaired when muscles of six CRF and control rats were exercised to tetany by stimulation of the sciatic nerve. Neither pHi nor the recovery of pHi differed between CRF and control rats. We conclude that pHi is maintained in muscle in uremia and that signals other than changing pHi must be necessary to disrupt metabolism.

Acidosis↗
PubMed1995

Interactions between L-arginine and L-glutamine change endothelial NO production. An effect independent of NO synthase substrate availability.

The effect of extracellular L-arginine and L-glutamine on nitric oxide (NO) release was studied in cultured bovine aortic endothelial cells and in rabbit aortic rings. Increasing L-arginine (0.01 to 10 mM) did not alter NO release from cultured endothelial cells or modify endothelium-dependent relaxation to acetylcholine in isolated vessels. L-Glutamine (0.6 and 2 mM) inhibited NO release from cultured cells (in response to bradykinin) and from aortic rings (in response to acetylcholine or ADP). L-Arginine (0.1-10 mM) dose-dependently reversed the L-glutamine inhibition of receptor-stimulated NO release in both models. In contrast to its inhibitory response to receptor-mediated stimuli, glutamine alone slightly potentiated NO release in both models when the calcium ionophore, A23187, was added. Furthermore, cultured cells incubated with L-arginine (0.01-10 mM), in the presence or absence of glutamine, released similar amounts of NO in response to A23187. L-Glutamine did not affect intracellular L-arginine levels. Neither D-glutamine nor D-arginine affected NO release or endothelium-dependent vascular relaxation. L-Glutamine had no effect on the activity of endothelial NOS assessed by L-arginine to L-citrulline conversion. These findings show that in the absence of L-glutamine, manipulating intracellular L-arginine levels over a wide range does not affect NO release. L-Glutamine in concentrations circulating in vivo may tonically inhibit receptor-mediated NO release by interfering with signal transduction. One mechanism by which L-arginine may enhance NO release is via reversal of the inhibitory effect of L-glutamine, but apparently independently of enhancing NO synthase substrate.

Acetylcholine↗
PubMed1995

Impaired cation transport in thymocytes of rats with chronic uremia includes the Na+/H+ antiporter.

To examine how uremia changes sodium, potassium, and proton transport, thymocytes from chronic renal failure (CRF) rats were studied. If alterations in cation transport associated with chronic uremia (CRF) extend to intracellular pH regulation, the susceptibility to the catabolic effects of acidosis might be increased. To evaluate the influence of acidosis, cation transport in thymocytes from normal rats with NH4Cl-induced acidosis was also studied. Ouabain-sensitive 86Rb influx in thymocytes from acidotic CRF rats was 32% lower than in control cells (P < 0.05), but intracellular sodium concentration was unchanged. This may be related to a 47 +/- 22% reduction in 22Na influx. In thymocytes from nonuremic, acidotic rats, ouabain-sensitive 86Rb influx was decreased 39% (P < 0.025), similar to the change in CRF. In CRF thymocytes, Na(+)-H+ antiporter activity in response to cell acidification (7.13 +/- 0.8 versus 9.42 +/- 0.8 mmol of H+/L per min; CRF versus control), or to osmotic shrinkage (0.43 +/- 0.09 versus 0.82 +/- 0.11 mmol of H+/L per min; CRF versus control), was significantly (P < 0.01) reduced. Buffering capacity at resting and acidic intracellular pH was unchanged by uremia, but Na+/H+ antiporter activity in response to acid loading or osmotic shrinkage was unchanged in thymocytes of nonuremic rats with metabolic acidosis. Thus, CRF reduces both Na/K-ATPase and Na+/H+ antiporter activities in rat thymocytes. The former may be secondary to reduced sodium influx. Impaired Na+/H+ antiporter activity is not caused by metabolic acidosis alone, whereas reduced Na/K-ATPase activity is found in both acidosis and uremia.

Animals↗