scholarly journals A Mathematical Model of Mitochondria in Proximal Tubule and Thick Ascending Limb Cells

2021 ◽  
Author(s):  
William Bell ◽  
Anita Layton
Keyword(s):  
Oxidative Phosphorylation ◽  
Proximal Tubule ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Complex Iii ◽  
Thick Ascending Limb ◽  
Metabolic Demand ◽  
Medullary Thick Ascending Limb ◽  
Baseline Activity ◽  
Lower Baseline

Mitochondria are a key player in several kinds of tissue injury, and are even the ultimate cause of certain diseases. In this work we introduce new models of mitochondrial ATP generation in multiple tissues, including liver hepatocytes and the medullary thick ascending limb in the kidney. Using this model, we predict these tissues' responses to hypoxia, uncoupling, ischemia-reperfusion, and oxidative phosphorylation dysfunction. Our results suggest mechanisms explaining differences in robustness of mitochondrial function across tissues. The medullary thick ascending limb and proximal tubule in the kidney both experience a high metabolic demand, while having lower baseline activity of oxidative phosphorylation relative to the liver. These factors make these tissues susceptible to dysfunction of Complex III. A lower baseline oxygen tension observed in the thick ascending limb makes it susceptible to Complex IV. On the other hand, since the liver lacks these risk factors, and has higher baseline rates of glycolysis, it is less susceptible to all kinds of oxidative phosphorylation dysfunction.

Potassium deprivation upregulates expression of renal basolateral Na+-HCO3 −cotransporter (NBC-1)

2000 ◽  
Vol 279 (3) ◽  
pp. F532-F543 ◽  
Author(s):  
Hassane Amlal ◽  
Khalid Habo ◽  
Manoocher Soleimani
Keyword(s):  
Proximal Tubule ◽  
Collecting Duct ◽  
Thick Ascending Limb ◽  
Mrna Levels ◽  
Time Intervals ◽  
Outer Medulla ◽  
Medullary Thick Ascending Limb ◽  
Medullary Collecting Duct ◽  
Potassium Deprivation ◽  
Expression And Activity

The purpose of the present experiments was to examine the effect of potassium deprivation on the expression of the renal basolateral Na+-HCO3 − cotransporter (NBC-1). Rats were placed on a K+-free diet for various time intervals and examined. NBC-1 mRNA levels increased by about threefold in the cortex ( P < 0.04) at 72 h of K+ deprivation and remained elevated at 21 days. NBC activity increased by ∼110% in proximal tubule suspensions, with the activity increasing from 0.091 in control to 0.205 pH/min in the K+-deprived group ( P < 0.005). The inner stripe of outer medulla and cells of medullary thick ascending limb of Henle (mTAL) showed induction of NBC-1 mRNA and activity in K+-deprived rats, with the activity in mTAL increasing from 0.010 in control to 0.133 pH/min in the K+-deprived group ( P < 0.004). K+ deprivation also increased NBC-1 mRNA levels in the renal papilla ( P < 0.02). We conclude that 1) K+ deprivation increases NBC-1 expression and activity in proximal tubule and 2) K+deprivation causes induction of NBC-1 expression and activity in mTAL tubule and inner medulla. We propose that NBC-1 likely mediates enhanced HCO3 − reabsorption in proximal tubule, mTAL, and inner medullary collecting duct in K+ deprivation and contributes to the maintenance of metabolic alkalosis in this condition.

31P nuclear magnetic resonance study of steady-state adenosine 5′-triphosphate levels during graded hypoxia in the isolated perfused rat kidney

1988 ◽  
Vol 74 (4) ◽  
pp. 437-448 ◽  
Author(s):  
P. J. Ratcliffe ◽  
Z. H. Endre ◽  
S. J. Scheinman ◽  
J. D. Tange ◽  
J. G. G. Ledingham ◽  
...  
Keyword(s):  
Steady State ◽  
Proximal Tubule ◽  
Oxygen Delivery ◽  
Rat Kidney ◽  
Thick Ascending Limb ◽  
Cellular Injury ◽  
Isolated Perfused Rat Kidney ◽  
Medullary Thick Ascending Limb ◽  
Henle's Loop ◽  
Perfused Rat Kidney

1. A model of controlled hypoxia in the isolated perfused rat kidney has been used to compare the extent of reduction in the steady-state level of adenosine 5′-triphosphate (ATP) from that initially observed with alterations in renal function and with the development of tubular cell injury. 2. ATP depletion was observed in response to decreased total oxygen delivery even when delivery greatly exceeded consumption and the venous oxygen tension remained in excess of 150 mmHg. 3. Increases in the fractional excretion of sodium occurred progressively below an apparent threshold value of whole kidney ATP of approximately 80% of the baseline. 4. With modestly decreased oxygen delivery, cellular injury was confined to deep proximal tubule and medullary thick ascending limb of Henle's loop. Severely decreased oxygen delivery rates were associated with cellular damage spreading throughout the cortex. 5. Even the smallest reductions in whole kidney ATP were associated with morphological damage to tubular cells. The extent of reduction in whole kidney ATP was closely correlated and approximately equivalent to the calculated volume of injured cells. 6. Our results indicate that reduction in whole kidney ATP during decreased oxygen delivery is a valid marker of the extent of injurious cellular hypoxia and are consistent with the view that cellular ATP concentrations in hypoxia are markedly inhomogeneous. They support the hypothesis that specific regions of the perfused kidney become critically hypoxic and develop cellular injury while overall oxygen delivery remains high. Areas at risk include deep proximal tubule as well as the medullary thick ascending limb of Henle's loop.

Abstract P269: Sodium Transporter Profile in Mice Lacking AT1A Receptors in the Renal Proximal Tubule

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Alicia A McDonough ◽  
Audrey K Izuhara ◽  
Zhidan Xiang ◽  
Donna L Ralph ◽  
Rishav Adhikari ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Renal Cortex ◽  
Immunoblot Analysis ◽  
Renal Proximal Tubule ◽  
Volume Flow ◽  
Thick Ascending Limb ◽  
Wild Type ◽  
Fluid Reabsorption ◽  
Lower Baseline ◽  
Sodium Transporter

We have reported that mice lacking AT1A receptors (KO) in renal proximal tubule (PT) have 10 mmHg lower baseline BP and less PT fluid reabsorption than wild type (WT). We tested the hypothesis that the lower BP is associated with less abundant renal Na transporters or regulators. Homogenates of renal cortex and medulla (n=6/group) were prepared and 1 and 1/2 protein amounts of each subjected to immunoblot analysis with specific antibodies and quantitated. Results for cortex and medulla, displayed as mean +/- SEM, normalized to mean abundance of WT=1 (*p <0.05), are summarized in figures. In KO vs. WT abundance of PT NHE3, the associated motor myosin VI, the paracellular NaCl transporter claudin 2, and the Na-HCO3 transporter NBCe1 are lower in KO; in the thick ascending limb (TAL) NKCC2 and its associated kinase SPAK are less abundant, and there is a tendency for lower DCT NCC and CCD ENaC in KO. The results support our hypothesis and suggest that KO of PT AT1R reduces transport routes not only in the PT but beyond the PT, in spite of increased volume flow from PT and lower BP.

scholarly journals Na–Pi cotransporter type I activity causes a transient intracellular alkalinization during ATP depletion in rabbit medullary thick ascending limb cells

2008 ◽  
Vol 86 (1-2) ◽  
pp. 36-45
Author(s):  
F. Jans ◽  
M. Ameloot ◽  
P. Wouters ◽  
P. Steels
Keyword(s):  
Cell Cultures ◽  
Ischemia Reperfusion ◽  
Apical Cell ◽  
Atp Depletion ◽  
Primary Cell ◽  
Type I ◽  
Thick Ascending Limb ◽  
Apical Cell Membrane ◽  
Primary Cell Cultures ◽  
Medullary Thick Ascending Limb

The cellular pathophysiology of renal ischemia–reperfusion injury was investigated in primary cell cultures from rabbit medullary thick ascending limb (MTAL). Metabolic inhibition (MI) was achieved with cyanide and 2-deoxyglucose. Sixty minutes of MI caused a profound but reversible decrease in intracellular concentration of ATP ([ATP]i). Intracellular pH (pHi) first decreased after initiation of MI, followed by a transient alkalinization. When [ATP]i reached its lowest value (<1% of control), the cells slowly acidified to reach a stable pHi of 6.92 after 50 min of MI. In the presence of EIPA (10 µmol/L), the pattern of changes in pHi was unchanged and acidification was not increased, indicating that the Na+/H+ exchangers were inactive during ATP depletion. When inorganic phosphate (Pi) or Na+ was omitted from the apical solutions during MI, the transient alkalinization was no longer observed and the cytosol slowly acidified. Experiments on Na+-dependent alkalinizations revealed the presence of a Na–Pi cotransporter in the apical cell membrane. With indirect immunofluorescence, the Na–Pi cotransporter expressed in these primary cell cultures could be identified as Na–Pi type I. Although the exact physiological role of Na–Pi type I still is unresolved, these experiments demonstrate that apical Na–Pi type I activity is increased at the onset of ATP depletion in MTAL cells.

Ischemia-reperfusion induces G-CSF gene expression by renal medullary thick ascending limb cells in vivo and in vitro

2004 ◽  
Vol 286 (6) ◽  
pp. F1193-F1201 ◽  
Author(s):  
Ying Zhang ◽  
Vanessa K. Woodward ◽  
John M. Shelton ◽  
James A. Richardson ◽  
Xin J. Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Thick Ascending Limb ◽  
Rnase Protection ◽  
Medullary Thick Ascending Limb ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Ischemic acute renal failure involves not only the kidney but also extrarenal organs such as the bone marrow that produces inflammatory cells. By ELISA and RNase protection assays, we now show that renal ischemia-reperfusion increases serum concentrations of granulocyte macrophage colony-stimulating factor (G-CSF) protein and increases both G-CSF mRNA and protein in the ischemic kidney. In situ hybridization localized the increased G-CSF mRNA to tubule cells, including medullary thick ascending limb cells (mTAL), in the outer medulla. We also show that mTAL produce G-CSF protein and increase G-CSF mRNA after stimulation by reactive oxygen species in vitro. The production of G-CSF by the kidney after ischemia-reperfusion provides a means of communication from the injured kidney to the bone marrow. This supports the known inflammatory response to ischemia.

Determinants of intrarenal oxygenation. I. Effects of diuretics

1994 ◽  
Vol 267 (6) ◽  
pp. F1059-F1062 ◽  
Author(s):  
M. Brezis ◽  
Y. Agmon ◽  
F. H. Epstein
Keyword(s):  
Blood Flow ◽  
Proximal Tubule ◽  
Ethacrynic Acid ◽  
Loop Diuretics ◽  
Thick Ascending Limb ◽  
O2 Consumption ◽  
Doppler Probe ◽  
Medullary Thick Ascending Limb ◽  
Medullary Blood Flow ◽  
Oxygen Tensions

To study renal cortical and medullary oxygen tensions, we used sensitive Clark-type O2 microelectrodes, inserted by micromanipulators into the cortex and medulla of kidneys of anesthetized rats. As previously reported, under basal conditions, medullary PO2 was significantly lower than cortical PO2. Furosemide, which inhibits reabsorptive transport in the medullary thick ascending limb, increased medullary PO2 from 16 +/- 4 to 35 +/- 4 mmHg (P < 0.0005) without altering cortical PO2. This effect, reproduced by ethacrynic acid and bumetanide, was selective for loop diuretics and was directly due to decreased tubular O2 consumption, since medullary blood flow was remarkably reduced by furosemide (-28 +/- 6% from baseline, P < 0.0001, as measured by a laser-Doppler probe). By contrast, acetazolamide, which decreases proximal tubule metabolism, selectively increased cortical PO2. These data are, in general, consistent with tubular metabolism as a major determinant of intrarenal oxygenation and suggest, in particular, that medullary reabsorptive work is at least in part responsible for renal medullary hypoxia.

scholarly journals Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine

2016 ◽  
Vol 310 (4) ◽  
pp. F294-F299 ◽  
Author(s):  
Michel Baum
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Chloride Transport ◽  
Bathing Solution ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Adrenergic Stimulation ◽  
Nacl Transport ◽  
Medullary Thick Ascending Limb ◽  
Stimulation Of

Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10−8 M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm−1·min−1, P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10−6 M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm−1·min−1 ( P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10−3 M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10−5 H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II.

scholarly journals P2X receptors trigger intracellular alkalization in isolated perfused mouse medullary thick ascending limb

2014 ◽  
Vol 213 (1) ◽  
pp. 277-284 ◽  
Author(s):  
P. I. A. Bruijn ◽  
M. Bleich ◽  
H. A. Praetorius ◽  
J. Leipziger
Keyword(s):  
P2x Receptors ◽  
Thick Ascending Limb ◽  
Medullary Thick Ascending Limb

scholarly journals High sodium intake increases HCO3− absorption in medullary thick ascending limb through adaptations in basolateral and apical Na+/H+ exchangers

2011 ◽  
Vol 301 (2) ◽  
pp. F334-F343 ◽  
Author(s):  
David W. Good ◽  
Thampi George ◽  
Bruns A. Watts
Keyword(s):  
Absorptive Capacity ◽  
Sodium Intake ◽  
Thick Ascending Limb ◽  
Acid Base Balance ◽  
High Sodium ◽  
High Sodium Intake ◽  
Medullary Thick Ascending Limb ◽  
Nhe1 Activity ◽  
Exchange Activity

A high sodium intake increases the capacity of the medullary thick ascending limb (MTAL) to absorb HCO3−. Here, we examined the role of the apical NHE3 and basolateral NHE1 Na+/H+ exchangers in this adaptation. MTALs from rats drinking H2O or 0.28 M NaCl for 5–7 days were perfused in vitro. High sodium intake increased HCO3− absorption rate by 60%. The increased HCO3− absorptive capacity was mediated by an increase in apical NHE3 activity. Inhibiting basolateral NHE1 with bath amiloride eliminated 60% of the adaptive increase in HCO3− absorption. Thus the majority of the increase in NHE3 activity was dependent on NHE1. A high sodium intake increased basolateral Na+/H+ exchange activity by 89% in association with an increase in NHE1 expression. High sodium intake increased apical Na+/H+ exchange activity by 30% under conditions in which basolateral Na+/H+ exchange was inhibited but did not change NHE3 abundance. These results suggest that high sodium intake increases HCO3− absorptive capacity in the MTAL through 1) an adaptive increase in basolateral NHE1 activity that results secondarily in an increase in apical NHE3 activity; and 2) an adaptive increase in NHE3 activity, independent of NHE1 activity. These studies support a role for NHE1 in the long-term regulation of renal tubule function and suggest that the regulatory interaction whereby NHE1 enhances the activity of NHE3 in the MTAL plays a role in the chronic regulation of HCO3− absorption. The adaptive increases in Na+/H+ exchange activity and HCO3− absorption in the MTAL may play a role in enabling the kidneys to regulate acid-base balance during changes in sodium and volume balance.

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