scholarly journals Alkaline intracellular pH activates AMPK-mTORC2 signaling to promote cell survival during growth factor limitation

2021 ◽  
Author(s):  
Dubek Kazyken ◽  
Stephen I Lentz ◽  
Diane C. Fingar
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Acid Solution ◽  
Cell Survival ◽  
Intracellular Ph ◽  
Cell Metabolism ◽  
Ph Sensing ◽  
Amino Acid Solution ◽  
Promote Cell Survival

mTORC2 controls cell metabolism and promotes cell survival, yet its upstream regulation by diverse cellular cues remains poorly defined. While considerable evidence indicates that mTORC1 but not mTORC2 responds dynamically to amino acid levels, several studies reported activation of mTORC2 signaling by amino acids, a paradox that remains unresolved. Following amino acid starvation, we noted that addition of a commercial amino acid solution but not re-feeding with DMEM containing amino acids increased mTORC2 signaling. Interestingly, the pH of the amino acid solution was ~ 10. These key observations enabled us to discover that alkaline intracellular pH (pHi) represents a previously unknown activator of mTORC2. Using a fluorescent pH-sensitive dye (cSNARF-1-AM) coupled to live-cell imaging, we demonstrate that alkaline extracellular pH (pHe) increases intracellular pHi, which increases mTORC2 catalytic activity and downstream signaling to Akt. Alkaline pHi also activates AMPK, a sensor of energetic stress. Functionally, alkaline pHi attenuates apoptosis caused by growth factor withdrawal, which requires AMPK in part and mTOR in full. Collectively, these findings reveal that alkaline pHi increases AMPK-mTORC2 signaling to promote cell survival during growth factor limitation. As elevated pHi represents an under-appreciated hallmark of cancer cells, alkaline pH sensing by AMPK-mTORC2 may contribute to tumorigenesis.

Effective Use of Amino Acid Dialysate over four Weeks in CAPD Patients

1983 ◽  
Vol 3 (2) ◽  
pp. 66-72 ◽  
Author(s):  
Arie Oren ◽  
George Wu ◽  
G. Harvey Anderson ◽  
Errol Marliss ◽  
Ramesh Khanna ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acid Solution ◽  
Serum Albumin ◽  
Hdl Cholesterol ◽  
Significant Rise ◽  
Protein Malnutrition ◽  
Metabolic Effects ◽  
Amino Acid Solution ◽  
Total Body

We studied the effectiveness, tolerance to, and beneficial metabolic effects of amino acid dialysate over an intermediate period in six CAPD patients. Two liters of 1% amino acid solution (Amino-Dianeal) were alternated with dialysate containing glucose. After four weeks there were significant increases in BUN (from 64 to 102 mg%), total body nitrogen (from 1333 to 1380 g), serum transferrin (from 175 to 222 mg%) and anion gap (from 15.1 to 17.3). Initially, there was a significant rise in HDL cholesterol, however, this was not sustained. No significant change was detected in total-body potassium, fasting serum albumin, triglyceride, insulin, glucagon, electrolytes, anthropometric measurements and daily ingestion of calories and proteins. During the study individual fasting, plasma amino acid levels showed significant increments in respect to histidine, tryptophan and glycine but alanine decreased. Several essential amino acids continued to show values below normal. Two hours after consumption of breakfast and concurrent infusion of the amino acid solution, the plasma levels of the amino acids in the dialysate peaked at emia, which develops in almost onehalf of the CAPD patients (7), and the significant weight gain observed in some of them. Furthermore, the daily losses of albumin and amino acids in the dialysate may induce protein malnutrition, especially if these losses are not replaced by an adequate daily protein intake. The presence of protein malnutrition in CAPD patients is indicated by the low serum albumin and total protein, and by the decrease in total body nitrogen over one year of CAPD (8).

Amino Acid Absorption following Intraperitoneal Administration in CAPD Patients

1981 ◽  
Vol 2 (3) ◽  
pp. 124-130 ◽  
Author(s):  
Paul F. Williams ◽  
Errol B. Marliss ◽  
G. Harvey Anderson ◽  
Arie Oren ◽  
Arthur N. Stein ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acid Solution ◽  
Intraperitoneal Administration ◽  
Amino Acid Solution ◽  
Dialysis Solution ◽  
Term Administration ◽  
Osmotic Agent ◽  
Amino Acid Levels

Six non-diabetic CAPD patients were infused over six hours with two litres of a dialysis solution containing 2 g/ dl amino acids (a mixture of essentials and non-essentials). The osmolality of the solution and the amount of ultrafiltration it induced were simiiar to that of a 4.25 g% dextrose Dianeal solution (control), suggesting that an amino acid solution is an efficient osmotic agent. By the end of the six-hour infusion, 80 to 90% of the amino acids present in the dialysis solution had been absorbed. One hour after the infusion was instituted, plasma amino acid levels increased threefold and subsequently decreased to near the initial value by the sixth hour. The amino acid solution was as effective as the dextrose solution in removing urea nitrogen, creatinine and potassium. Our data indicate that intraperitoneal administration of amino acids is effective and well-tolerated in patients on CAPD. We believe further work should be done to determine whether long-term administration of amino acids by this route will improve the nutritional status of these patients and prevent the side effects of daily absorption of large amounts of glucose.

Modification of An Amino Acid Solution for Peritoneal Dialysis to Reduce Risk of Acidemia

1997 ◽  
Vol 17 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Michael Jones ◽  
Roberto Kalil ◽  
Peter Blake ◽  
Leo Martis ◽  
Dimitrios G. Oreopoulos
Keyword(s):  
Amino Acids ◽  
Body Weight ◽  
Peritoneal Dialysis ◽  
Amino Acid ◽  
Acid Solution ◽  
Long Term Effects ◽  
Amino Acid Solution ◽  
Nutritional Benefits ◽  
Modified Formula

Objective Some patients develop a mild acidemia during treatment with amino acid-based peritoneal dialysis solutions due to hydrogen ion produced by metabolism of lysine, arginine, and methionine. In this study we modified the formulation of such a solution by reducing these amino acids and adding anionic amino acids so as to provide minimal net acid production. Design A modified formula (MF) was compared to a conventional formula (CF) of the solution in a randomized crossover study in 12 stable continuous ambulatory peritoneal dialysis patients. Patients were given each solution for 14 days without a wash-out period. Each patient replaced one or two dextrose dialysis exchanges with amino acid solution, depending upon oral protein intake and body weight. Total intake (oral protein plus amino acids absorbed) was equivalent to 1.1 -1.3 g protein/kg body weight/day.Plasma bicarbonate and urea were assessed at the beginning and end of each 14-day period. Results In the group as a whole, without regard to the order in which the solutions were given, patients had a decrease in serum bicarbonate with CF and an increase in bicarbonate when they received MF. Similar trends were observed regardless of the order in which the solutions were administered. Serum urea did not differ between the two solutions. Conclusion The results suggest that patients are less prone to develop acidemia when receiving MF as opposed to CF. Further studies will be necessary to determine the long-term effects and the relative nutritional benefits of the two solutions.

Short-term studies on the use of amino acids as an osmotic agent in continuous ambulatory peritoneal dialysis

1987 ◽  
Vol 73 (5) ◽  
pp. 471-478 ◽  
Author(s):  
T. H. J. Goodship ◽  
S. Lloyd ◽  
P. W. McKenzie ◽  
M. Earnshaw ◽  
I. Smeaton ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acid Solution ◽  
Serum Insulin ◽  
Branched Chain Amino Acids ◽  
High Concentration ◽  
Short Term ◽  
Amino Acid Solution ◽  
Metabolic Complications ◽  
Branched Chain

1. A 1% amino acid dialysis solution with a high concentration of the branched-chain amino acids has been compared with 1.36% glucose in short-term studies. 2. The 1% amino acid solution was as effective an agent as 1.36% glucose with respect to ultrafiltration and clearance of creatinine, urea and potassium. 3. Levels of branched-chain amino acids rose to the upper end of the normal range within 1 h and remained at this level over the entire period of the study. Total and non-essential amino acids had returned to baseline by the end of the cycle. 4. Blood glucose rose to significantly greater levels during the 1.36% glucose exchange than during the 1% amino acid exchange. There was an increase in serum insulin levels during both cycles; this was significantly greater with the 1% amino acid solution than the 1.36% glucose. 5. There was no evidence of short-term metabolic complications with the 1% amino acid solution.

Differential Effects of Amino Acids on the Isolated Perfused Rat Kidney

1990 ◽  
Vol 79 (4) ◽  
pp. 381-386 ◽  
Author(s):  
A. A. El Sayed ◽  
J. Haylor ◽  
A. M. El Nahas
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acid Solution ◽  
Time Dependent ◽  
Inulin Clearance ◽  
Sodium Glutamate ◽  
Amino Acid Solution ◽  
Control Series ◽  
Perfusate Flow ◽  
Arginine Hydrochloride

1. The direct effects of individual amino acids, including glycine (a neutral amino acid), l-glutamic acid (an acidic amino acid), l-leucine (a neutral, branched-chain amino acid) and l-arginine (a basic amino acid), on renal function were compared with a mixed amino acid solution by using the isolated rat kidney perfused with a physiological saline solution containing 6.7% (w/v) albumin and a basal level of 2 mmol/l mixed amino acids. 2. In a control series, the renal perfusate flow was stable but the glomerular filtration rate, as measured by [14C]inulin clearance, declined with time. A stable glomerular filtration rate could be obtained by increasing the basal perfusate amino acid concentration to 14 mmol/l. 3. The addition of 6 mmol/l mixed amino acids produced a sustained increase in renal perfusate flow and an increase in [14C]inulin clearance, reversing its time-dependent fall. Sodium reabsorption was enhanced, but, unlike the control series, no increase in fractional albumin excretion was obtained. 4. Renal perfusate flow was increased by glycine (6 mmol/l), l-arginine hydrochloride (6 mmoll) and sodium glutamate (6 mmol/l) but remained unaffected by l-leucine. The vasodilatation induced by l-arginine hydrochloride and sodium glutamate was not sustained. 5. The time-dependent fall in [14C]inulin clearance was prevented by glycine, l-arginine and glutamic acid, but not by l-leucine. l-Arginine hydrochloride, like the mixed amino acid solution, produced a significant increase in [14C]inulin clearance. 6. The fractional reabsorption of sodium was increased by glycine and l-leucine, was unaffected by sodium glutamate and was decreased by l-arginine hydrochloride. The time-dependent fall in the fractional excretion of albumin seen in the control series was, however, reversed by all individual amino acids. 7. The results indicate that amino acids can produce renal vasodilatation and hyperfiltration by a direct effect on the kidney, independent of the release of systemic hormones. Individual amino acids, however, differ in their contribution to the response elicited by a mixed amino acid solution. The use of individual amino acids to mimic the renal response to dietary protein in vivo may therefore be inappropriate.

Plasma Amino Acids in Patients with Acute Nonlymphocytic Leukemia Receiving Parenteral Nutrition

1993 ◽  
Vol 27 (2) ◽  
pp. 146-150
Author(s):  
Michael L. Christensen ◽  
Julienne Burgess ◽  
Richard A. Helms ◽  
Joseph Mirro ◽  
David K. Kalwinsky ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Parenteral Nutrition ◽  
Acid Solution ◽  
Plasma Amino Acid ◽  
Acid Solutions ◽  
Acute Nonlymphocytic Leukemia ◽  
Amino Acid Solution ◽  
Amino Acid Solutions ◽  
Amino Acid Concentrations

Objective To assess the effect of parenteral amino acid solutions on plasma amino acid concentrations in patients with acute nonlymphocytic leukemia (ANLL) receiving parenteral nutrition (PN). Design Ten patients were studied at diagnosis, on the morning PN was started, and three times during PN therapy coinciding with the sequential administration of three different amino acid solutions (Aminosyn, FreAmine HBC, and TrophAmine). The order of amino acid solution administration in each patient was by a randomized, block design. Results The patients were undergoing identical intensive induction therapy. There was no significant difference in the number of days they received PN or the amount of protein or calories received during the three PN study periods. At diagnosis, phenylalanine and glutamic acid concentrations were elevated compared with previously published normal values and remained elevated at all observation times. During PN, asparagine, aspartic acid, and tyrosine concentrations were significantly lower with all three amino acid solutions compared with their concentrations at diagnosis. Glycine and threonine concentrations were also significantly lower with FreAmine HBC and TrophAmine administration and cysteine concentrations were significantly lower with FreAmine HBC administration than at the time of diagnosis. Aminosyn was associated with plasma amino acid concentrations most similar to those measured at diagnosis. Conclusions These results indicate that most amino acid concentrations fall within the normal range at diagnosis in the ANLL patients studied. Plasma concentrations for certain amino acids can be influenced by the amino acid solution used in PN. Further understanding of the derangements in amino acid metabolism and the influence of parenterally administered amino acid solutions on plasma amino acid concentrations may lead to improvements in the nutritional support of cancer patients.

Mediators of the direct effects of amino acids on the rat kidney

1991 ◽  
Vol 81 (3) ◽  
pp. 427-432 ◽  
Author(s):  
A. A. El Sayed ◽  
J. Haylor ◽  
A. M. El Nahas
Keyword(s):  
Nitric Oxide ◽  
Amino Acids ◽  
Amino Acid ◽  
Methyl Ester ◽  
Acid Solution ◽  
Rat Kidney ◽  
Inulin Clearance ◽  
Sodium Reabsorption ◽  
Amino Acid Solution ◽  
Perfusate Flow

1. The response of the isolated rat kidney to a mixed amino acid solution was examined in the presence of three renal autacoid inhibitors, indomethacin (a cyclo-oxygenase inhibitor), sulpiride (a dopamine antagonist) and l-nitroarginine methyl ester (an inhibitor of nitric oxide synthesis). 2. Increasing the concentration of the mixed amino acid solution perfusing the kidney from 2 to 8 mmol/l (n = 6) produced a sustained increase in renal perfusate flow (P < 0.01) and reversed the time-dependent fall in [14C]inulin clearance (P < 0.01) demonstrated in kidneys perfused with 2 mmol/l mixed amino acids alone. A significant increase in the fractional sodium reabsorption and decrease in the fractional albumin excretion was also observed. 3. Indomethacin (10−4 mol/l, n = 6) produced partial (50%) inhibition of the effect of mixed amino acids on [14C]inulin clearance, but did not influence their ability to increase renal perfusate flow. 4. Sulpiride (0.7 μmol min−1 kg−1, n = 6) produced partial inhibition of the effect of mixed amino acids on both [14C]inulin clearance and renal perfusate flow by 60% and 50%, respectively. Sulpiride also entirely inhibited the reduction in fractional albumin excretion. 5. l-Nitroarginine methyl ester (10−4 mol/l, n = 6) completely inhibited the effect of mixed amino acids on [14C]inulin clearance, but did not inhibit the increase in renal perfusate flow, even though the basal vascular resistance was markedly enhanced. l-Nitroarginine methyl ester also inhibited the increase in fractional sodium reabsorption produced by the mixed amino acids. 6. It is concluded that prostaglandins, dopamine and nitric oxide may all have a role to play in the direct effect of mixed amino acids on renal function. This does not, however, preclude further modification by additional stimuli generated in vivo.

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