Effects of NH4Cl intake on renal growth in rats: role of MAPK signalling pathway

Bento, Leda Márcia Araújo; Carvalheira, José Barreto Campello; Menegon, Leonardo Fantinato; Saad, Mário J.A.; Gontijo, José Antônio Rocha

doi:10.1093/ndt/gfi133

Cited by 13 publications

(15 citation statements)

References 20 publications

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“…In this regard, we have previously shown that chronic metabolic acidosis, caused by NH 4 Cl feeding, leads to nephron hypertrophy and to a decreased watersalt reabsorption by the kidneys [1,25,26]. Since renal ion tubule transport is highly dependent on mitochondrial energy and because mitochondria have been implicated in a variety of metabolic disorders, we examined mitochondrial energy-linked functions in chronic metabolic acidotic rats.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies in rats [1,2] metabolic acidosis induced by NH 4 Cl resulted in an absolute increase in kidney mass associated with disturbances in renal sodium handling that were preceded by activation of kidney MAPK/ERKs signalling pathways. Under these acidotic conditions, the altered renal electrolyte handling may have resulted from a lack of energy availability for ion transport due to the high energy demand for renal anabolic processes [1].…”

Section: Introductionmentioning

confidence: 94%

“…Indeed, inhibition of Na þ -K þ -ATPase and, hence, a decrease in sodium tubule transport by the kidney is associated with increased rates of gluconeogenesis [9]. These findings suggest that energy-requiring processes, such as renal growth, sodium transport and gluconeogenesis compete for the available energy in nephron tubules and could explain the striking natriuresis observed under chronic acidosis [1]. Since respiration is the main source of energy supply for renal ion tubule transport, the altered renal Na þ and K þ handling under acidotic conditions may result from alterations in mitochondrial bioenergetics.…”

Section: Introductionmentioning

confidence: 96%

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Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats

Bento

Fagian

Vercesi

et al. 2007

Nephrology Dialysis Transplantation

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Background. We have previously shown that chronic metabolic acidosis, induced in rats by NH 4 Cl feeding, leads to nephron hypertrophy and to a decreased water-salt reabsorption by the kidneys. Since mitochondria are the main source of metabolic energy that drives ion transport in kidney tubules, we examined energy-linked functions (respiration, electrochemical membrane potential and coupling between respiration and ADP phosphorylation) in mitochondria isolated from rat kidney and liver at 48 h after metabolic acidosis induced by NH 4 Cl. Methods. Mitochondria isolated from the kidneys and liver of metabolic acidotic rats, induced by NH 4 Cl, was used to study of the oxygen consumption by Clarktype electrode, mitochondrial electrical transmembrane potential estimated by the safranine O method and the variations in free medium Ca 2+ concentrations examined by absorbance spectrum of Arsenazo III set at the 675-685 nm wavelength pair. Results. Whole kidney and liver mitochondria isolated from 48 h acidotic rats presented higher resting respiration, lower respiratory control and a lower ADP/O ratio than controls. These differences in mitochondrial coupling, between respiration and oxidative phosphorylation (ATP synthesis), were totally corrected when experiments were carried out in the presence of carboxyatractyloside, GDP and BSA, indicating that mitochondrial uncoupling proteins are more active in acidotic rat kidneys. Interestingly, determination of Ca 2þ transport demonstrated a faster rate of initial Ca 2þ uptake by acidotic kidney mitochondria, which resulted in a lower concentration of extra-mitochondrial Ca 2þ under steady-state conditions (Ca 2þ set point) when compared with control mitochondria.In contrast, there were no significant differences in the rates of Na þ or ruthenium red induced Ca 2þ efflux. Conclusions. We suggest that the mild uncoupling and higher Ca 2þ accumulation represents an adaptation of the mitochondria to cope with conditions of oxidative stress and high cytosolic Ca 2þ , which are associated with a decreased efficiency of oxidative phosphorylation that may explain, at least in part, the striking natriuresis observed under chronic acidosis. Finally, there were no changes in Ca 2þ transport or coupling in liver mitochondria isolated from the acidotic rats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 96%

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Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats

Bento

Fagian

Vercesi

et al. 2007

Nephrology Dialysis Transplantation

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“…Interestingly, ERK activation in this proximal tubule like cell is associated with NHE3 inhibition, not unlike NHE3 inhibition and reduced bicarbonate absorption by ERK activation in the thick ascending limb of the nephron [23]. This effect plus ERK activation dependent depolarization of mitochondria may contribute to the profound natriuresis observed in vivo with metabolic acidosis [5,[24][25][26]. Metabolic base generation requires that glutamate be oxidized by glutamate dehydrogenase within the mitochondrial matrix and coupled to Complex I via NADH+H + .…”

Section: Discussionmentioning

confidence: 99%

“…Extracellular Signal-Regulated Kinase (ERK) activation occurs in kidney cells in response to metabolic acidosis in vivo as well as in cultured kidney cells [5][6][7] suggesting ERK activation plays a role in physiological responses. However, the underlying mechanisms relating TRO-induced ERK activation and cellular acidosis requires further clarification.…”

Section: Introductionmentioning

confidence: 99%

Troglitazone Induced Cytosolic Acidification via Extracellular Signal-Response Kinase Activation and Mitochondrial Depolarization: Complex I Proton Pumping Regulates Ammoniagenesis in Proximal Tubule-like LLC-PK<sub>1</sub> Cells

Oliver

Friday

Turturro

et al. 2008

Cell Physiol Biochem

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Purpose: To determined the mechanism(s) through which troglitazone induces cytosolic acidification and glutamine-dependent ammoniagenesis in pig kidney derived LLC-PK1 cells. Experimental Design: Acute experiments measured acid extrusion, acid production and simultaneous Extracellular Signal-Regulated Kinase activation. TRO-enhanced acid production was correlated with mitochondrial membrane potential and rotenone and 5-(N-ethyl-N-isopropyl) amiloride, were employed to test specifically the role of Complex I proton pumping. Chronic experiments correlated inhibitors of Complex I with prevention of TRO-increased ammoniagenesis and affects on glutamine metabolism. Results: Exposure to TRO acutely activated Extracellular Signal-Regulated Kinase in a dose dependent manner associated with a fall in spontaneous cytosolic pH. Cytosolic acidosis was associated with both an increase in acid production and inhibition of sodium/hydrogen ion exchanger -mediated acid extrusion. Preventing TRO-induced Extracellular Signal-Regulated Kinase activation with Mitogen Activated Protein Kinase Kinase inhibitors blocked the increase in acid production, restored sodium/hydrogen ion exchanger-activity and prevented cytosolic acidification. Mechanistically, increased acid production was associated with a rapid mitochondrial depolarization and Complex I proton pumping. Blocking Extracellular Signal-Regulated Kinase activation prevented both the fall in Ψm and the increased acid production suggesting that the former underlies the accelerated mitochondrial “acid production”. Mitochondrial Complex I inhibitors EIPA and rotenone prevented increased acid production despite Extracellular Response Kinase activation and reduced sodium/hydrogen ion activity. Inhibition of Complex I prevented TRO’s effects on glutamine metabolism. Conclusion:TRO induces cellular acidosis through Extracellular Signal-Regulated Kinase activation-associated acid production and impaired acid extrusion. Acutely, increased acid production reflects mitochondrial Complex I proton pumping into the cytosol while chronically Complex I activity appears coupled to mitochondrial glutamate uptake and oxidation to ammonium at the expense of cytosolic transamination and alanine formation in these proximal tubule-like cells.

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Ammonia toxicity: from head to toe?

et al. 2016

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Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.

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Effects of NH4Cl intake on renal growth in rats: role of MAPK signalling pathway

Cited by 13 publications

References 20 publications

Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats

Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats

Troglitazone Induced Cytosolic Acidification via Extracellular Signal-Response Kinase Activation and Mitochondrial Depolarization: Complex I Proton Pumping Regulates Ammoniagenesis in Proximal Tubule-like LLC-PK<sub>1</sub> Cells

Ammonia toxicity: from head to toe?

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