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American Journal of Physiology. Renal... Jun 2023Phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis,...
Phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis, and cataplerosis in the liver. Kidney proximal tubule cells display high expression of this enzyme, whose importance is currently not well defined. We generated PCK1 kidney-specific knockout and knockin mice under the tubular cell-specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal conditions and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia, and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1-deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule, and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigation of PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid-base control, mitochondrial function, and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function. Phosphoenolpyruvate carboxykinase 1 (PCK1) is highly expressed in the proximal tubule. We show here that this enzyme is crucial for the maintenance of normal tubular physiology, lactate, and glucose homeostasis. PCK1 is a regulator of acid-base balance and ammoniagenesis. Preventing PCK1 downregulation during renal injury improves renal function, rendering it an important target during renal disease.
Topics: Animals; Mice; Acidosis; Glucose; Kidney; Lactates; Mitochondria; Phosphoenolpyruvate; Phosphoenolpyruvate Carboxykinase (GTP)
PubMed: 37102687
DOI: 10.1152/ajprenal.00038.2023 -
Current Eye Research Jul 2018Changes in retinal pH may contribute to a variety of eye diseases. To study the effect of acidosis alone, we induced systemic metabolic acidosis and hypothesized that...
PURPOSE
Changes in retinal pH may contribute to a variety of eye diseases. To study the effect of acidosis alone, we induced systemic metabolic acidosis and hypothesized that the retina would respond with altered expression of genes involved in acid/base regulation.
METHODS
Systemic metabolic acidosis was induced in Long-Evans rats for up to 2 weeks by adding NHCl to the drinking water. After 2 weeks, venous pH was 7.25 ± 0.08 (SD) and [HCO] was 21.4 ± 4.6 mM in acidotic animals; pH was 7.41 ± 0.03 and [HCO] was 30.5 ± 1.0 mM in controls. Retinal mRNAs were quantified by quantitative reverse transcription polymerase chain reaction. Protein was quantified with Western blots and localized by confocal microscopy. Retinal [H] was measured in vivo with pH microelectrodes in animals subjected to metabolic acidosis and in controls.
RESULTS
NHCl in drinking water or given intravenous was effective in acidifying the retina. Cariporide, a blocker of Na/H exchange, further acidified the retina. Metabolic acidosis for 2 weeks led to increases of 40-100% in mRNA for carbonic anhydrase isoforms II (CA-II) and XIV (CA-XIV) and acid-sensing ion channels 1 and 4 (ASIC1 and ASIC4) (all p < 0.005). Expression of anion exchange protein 3 (AEP-3) and Na/H exchanger (NHE)-1 also increased by ≥50% (both p < 0.0001). Changes were similar after 1 week of acidosis. Protein for AEP-3 doubled. NHE-1 co-localized with vascular markers, particularly in the outer plexiform layer. CA-II was located in the neural parenchyma of the ganglion cell layer and diffusely in the rest of the inner retina.
CONCLUSIONS
The retina responds to systemic acidosis with increased expression of proton and bicarbonate exchangers, carbonic anhydrase, and ASICs. While responses to acidosis are usually associated with renal regulation, these studies suggest that the retina responds to changes in local pH presumably to control its acid/base environment in response to systemic acidosis.
Topics: Acidosis; Animals; Blotting, Western; Disease Models, Animal; Electroretinography; Eye Proteins; Gene Expression Regulation; Hydrogen-Ion Concentration; Immunohistochemistry; Male; RNA; Rats; Rats, Long-Evans; Retina; Reverse Transcriptase Polymerase Chain Reaction; Sodium-Hydrogen Exchangers
PubMed: 29641914
DOI: 10.1080/02713683.2018.1458882 -
Kidney & Blood Pressure Research 2020Metabolic acidosis (MA) is a common complication in kidney transplantation (KTx). It is more prevalent in KTx than in CKD, and it occurs at higher glomerular filtration... (Review)
Review
BACKGROUND
Metabolic acidosis (MA) is a common complication in kidney transplantation (KTx). It is more prevalent in KTx than in CKD, and it occurs at higher glomerular filtration rates. The pathophysiologic understanding of MA in KTx and its clinical impact has been highlighted by few recent studies. However, no guidelines exist yet for the treatment of MA after KTx.
SUMMARY
MA in KTx seems to share pathophysiologic mechanisms with CKD, such as impaired ammoniagenesis. Additional kidney transplant-specific factors seem to alter not only the prevalence but also the phenotype of MA, which typically shows features of renal tubular acidosis. There is evidence that calcineurin inhibitors, immunological factors, process of donation, donor characteristics, and diet may contribute to MA occurrence. According to several mainly observational studies, MA seems to play a role in disturbed bone metabolism, cardiovascular morbidity, declining graft function, and mortality. A better understanding of the pathophysiology and evidence from randomized controlled trials, in particular, are needed to clarify the role of MA and the potential benefit of alkali treatment in KTx. Alkali therapy might not only be beneficial but also cost effective and safe. Key Messages: MA seems to be associated with several negative outcomes in KTx. A deeper understanding of the pathophysiology and clinical consequences of MA in KTx is crucial. Clinical trials will have to determine the potential benefits of alkali therapy.
Topics: Acidosis; Animals; Disease Management; Glomerular Filtration Rate; Humans; Kidney Transplantation; Renal Insufficiency, Chronic; Risk Factors
PubMed: 33040055
DOI: 10.1159/000510158 -
Kidney360 Nov 2022Obesity is a recently identified risk factor for metabolic acidosis and anion gap elevations in the absence of CKD. Metabolic acidosis is a treatable condition with...
BACKGROUND
Obesity is a recently identified risk factor for metabolic acidosis and anion gap elevations in the absence of CKD. Metabolic acidosis is a treatable condition with substantial adverse effects on human health. Additional investigations are needed to characterize at-risk populations and explore potential mechanisms. We hypothesized metabolic syndrome (MetS) and waist circumference (WC) would be closely associated with this pathology.
METHODS
Adult participants from NHANES 1999-2018 meeting study criteria were compiled as main (=31,163) and fasting (=12,860) cohorts. Regression models adjusted for dietary acid, eGFR, and other factors examined associations of WC and MetS features with anion gap metabolic acidosis and its components (serum bicarbonate ≤23 mEq/L and anion gap >95th percentile).
RESULTS
Greater WC and MetS features were associated with progressively lower bicarbonate, higher anion gap, and greater odds ratios (OR) of metabolic acidosis (MA) and anion gap metabolic acidosis (AGMA). Compared with the reference, participants with the highest WC had ORs for MA and AGMA of 2.26; 95% CI, 1.96 to 2.62 and 2.89; 95% CI, 1.97 to 4.21; those with three and four versus zero MetS features had ORs for AGMA of 2.52; 95% CI, 1.95 to 2.94 and 3.05; 95% CI, 2.16 to 3.82. Associations of body mass index with outcomes were attenuated or absent after adjustment for WC or MetS. Findings were preserved after excluding eGFR <90 ml/min per 1.73 m and albuminuria. A lower MA cutoff (<22 mEq/L) raised the estimate of association between MetS and MA (OR for three and four vs zero features: 3.56; 95% CI, 2.53 to 5.02 and 5.44; 95% CI, 3.66 to 8.08).
CONCLUSIONS
Metabolic diseases are characterized by metabolic acidosis and anion gap elevations. Metabolic dysfunction may predispose patients without CKD to systemic acidosis from endogenous sources. Comprehensive acid-base analyses may be informative in patients with metabolic diseases.
Topics: Humans; Adult; Obesity, Abdominal; Metabolic Syndrome; Acid-Base Equilibrium; Bicarbonates; Nutrition Surveys; Acidosis; Renal Insufficiency, Chronic
PubMed: 36514392
DOI: 10.34067/KID.0002402022 -
Clinical Journal of the American... Sep 2014The human kidneys produce approximately 160-170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by... (Review)
Review
The human kidneys produce approximately 160-170 L of ultrafiltrate per day. The proximal tubule contributes to fluid, electrolyte, and nutrient homeostasis by reabsorbing approximately 60%-70% of the water and NaCl, a greater proportion of the NaHCO3, and nearly all of the nutrients in the ultrafiltrate. The proximal tubule is also the site of active solute secretion, hormone production, and many of the metabolic functions of the kidney. This review discusses the transport of NaCl, NaHCO3, glucose, amino acids, and two clinically important anions, citrate and phosphate. NaCl and the accompanying water are reabsorbed in an isotonic fashion. The energy that drives this process is generated largely by the basolateral Na(+)/K(+)-ATPase, which creates an inward negative membrane potential and Na(+)-gradient. Various Na(+)-dependent countertransporters and cotransporters use the energy of this gradient to promote the uptake of HCO3 (-) and various solutes, respectively. A Na(+)-dependent cotransporter mediates the movement of HCO3 (-) across the basolateral membrane, whereas various Na(+)-independent passive transporters accomplish the export of various other solutes. To illustrate its homeostatic feat, the proximal tubule alters its metabolism and transport properties in response to metabolic acidosis. The uptake and catabolism of glutamine and citrate are increased during acidosis, whereas the recovery of phosphate from the ultrafiltrate is decreased. The increased catabolism of glutamine results in increased ammoniagenesis and gluconeogenesis. Excretion of the resulting ammonium ions facilitates the excretion of acid, whereas the combined pathways accomplish the net production of HCO3 (-) ions that are added to the plasma to partially restore acid-base balance.
Topics: Acidosis, Renal Tubular; Biological Transport, Active; Humans; Kidney Tubules, Proximal; Phosphates; Sodium Bicarbonate; Sodium Chloride
PubMed: 23908456
DOI: 10.2215/CJN.10391012 -
Nutrients May 2018Recent epidemiological findings suggest that high levels of dietary acid load can affect insulin sensitivity and glucose metabolism. Consumption of high protein diets... (Review)
Review
Recent epidemiological findings suggest that high levels of dietary acid load can affect insulin sensitivity and glucose metabolism. Consumption of high protein diets results in the over-production of metabolic acids which has been associated with the development of chronic metabolic disturbances. Mild metabolic acidosis has been shown to impair peripheral insulin action and several epidemiological findings suggest that metabolic acid load markers are associated with insulin resistance and impaired glycemic control through an interference intracellular insulin signaling pathways and translocation. In addition, higher incidence of diabetes, insulin resistance, or impaired glucose control have been found in subjects with elevated metabolic acid load markers. Hence, lowering dietary acid load may be relevant for improving glucose homeostasis and prevention of type 2 diabetes development on a long-term basis. However, limitations related to patient acid load estimation, nutritional determinants, and metabolic status considerably flaws available findings, and the lack of solid data on the background physiopathology contributes to the questionability of results. Furthermore, evidence from interventional studies is very limited and the trials carried out report no beneficial results following alkali supplementation. Available literature suggests that poor acid load control may contribute to impaired insulin sensitivity and glucose homeostasis, but it is not sufficiently supportive to fully elucidate the issue and additional well-designed studies are clearly needed.
Topics: Acid-Base Equilibrium; Acidosis; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Diet, High-Protein; Homeostasis; Humans; Insulin; Insulin Resistance; Muscle, Skeletal; Randomized Controlled Trials as Topic
PubMed: 29762478
DOI: 10.3390/nu10050618 -
Nutrients Jul 2021Metabolic acidosis is a severe complication of chronic kidney disease (CKD) which is associated with nefarious impairments such as bone demineralization, muscle wasting,... (Review)
Review
Metabolic acidosis is a severe complication of chronic kidney disease (CKD) which is associated with nefarious impairments such as bone demineralization, muscle wasting, and hormonal alterations, for example, insulin resistance. Whilst it is possible to control this condition with alkali treatment, consisting in the oral administration of sodium citrate or sodium bicarbonate, this type of intervention is not free from side effects. On the contrary, opting for the implementation of a targeted dietetic-nutritional treatment for the control of CKD metabolic acidosis also comes with a range of additional benefits such as lipid profile control, increased vitamins, and antioxidants intake. In our review, we evaluated the main dietary-nutritional regimens useful to counteract metabolic acidosis, such as the Mediterranean diet, the alkaline diet, the low-protein diet, and the vegan low-protein diet, analyzing the potentialities and limits of every dietary-nutritional treatment. Literature data suggest that the Mediterranean and alkaline diets represent a valid nutritional approach in the prevention and correction of metabolic acidosis in CKD early stages, while the low-protein diet and the vegan low-protein diet are more effective in CKD advanced stages. In conclusion, we propose that tailored nutritional approaches should represent a valid therapeutic alternative to counteract metabolic acidosis.
Topics: Acid-Base Equilibrium; Acidosis; Diet; Diet, Mediterranean; Diet, Protein-Restricted; Diet, Vegan; Humans; Nutrition Therapy; Renal Insufficiency, Chronic
PubMed: 34444694
DOI: 10.3390/nu13082534 -
Lakartidningen Oct 2017Alcoholic ketoacidosis - a review A chronic alcoholic with severe metabolic acidosis presents a difficult diagnostic problem in the emergency room. Over and above... (Review)
Review
Alcoholic ketoacidosis - a review A chronic alcoholic with severe metabolic acidosis presents a difficult diagnostic problem in the emergency room. Over and above methanol- and ethylene glycol intoxication, alcoholic ketoacidosis is a common but less recognized etiology. The disorder occurs in alcoholics who have had a recent binge drinking followed by the abrupt cessation of alcohol consumption because of abdominal pain and vomiting, with resulting dehydration, starvation, and then a β-hydroxybutyrate dominated ketoacidosis. Laboratory results may be misleading as the common urine-ketone tests may be negative or only weakly positive, since they only respond to acetoacetate. The short-term prognosis is good if treatment including replacement of fluid, electrolytes, glucose and thiamine is provided. However, recent studies have indicated that alcoholic ketoacidosis may be a significant cause of mortality in patients with alcohol dependence.
Topics: Alcoholism; Disease Management; Humans; Ketones; Ketosis
PubMed: 28994854
DOI: No ID Found -
Nephrology, Dialysis, Transplantation :... May 2016Chronic metabolic acidosis (CMA) is a common complication of the more advanced stages of chronic kidney diseases (CKD), and is associated with morbidity and mortality of... (Review)
Review
Chronic metabolic acidosis (CMA) is a common complication of the more advanced stages of chronic kidney diseases (CKD), and is associated with morbidity and mortality of CKD patients and possibly with the progression of renal disease. Nevertheless, there is limited evidence or information on the prevalence, the potential causal factors, the clinical impact and the effects of correction of CMA in kidney transplant recipients. In this review, we briefly look at the more relevant, though scanty, studies which have, over time, addressed the above-mentioned points, with the hope that in the future the interest of transplant nephrologists and surgeons will grow towards this unreasonably neglected issue.
Topics: Acidosis; Humans; Kidney Diseases; Kidney Transplantation
PubMed: 25934992
DOI: 10.1093/ndt/gfv098 -
International Journal of Molecular... Feb 2024A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense... (Review)
Review
A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense against metabolic acidosis, both as an intracellular and extracellular buffer, as well as in the renal excretion of excess acid in the form of urinary titratable acid. The skeleton acts as an extracellular buffer in states of metabolic acidosis, as the bone matrix demineralizes, leading to bone apatite dissolution and the release of phosphate, calcium, carbonate, and citrate into the circulation. The renal handling of calcium, phosphate and citrate is also affected, with resultant hypercalciuria, hyperphosphaturia and hypocitraturia.
Topics: Humans; Calcium; Kidney; Acidosis; Citric Acid; Kidney Diseases; Citrates; Calcium, Dietary; Phosphates
PubMed: 38396761
DOI: 10.3390/ijms25042081