A mathematical model of the rat nephron: glucose transport

Weinstein, Alan M.

doi:10.1152/ajprenal.00505.2014

Cited by 39 publications

(41 citation statements)

References 43 publications

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“…Owing to the scarcity of data (anatomic, transport, electrochemical, etc.) in the human kidney relative to the rat, all detailed mathematical models of the mammalian kidney have been built for the rat [19, 18, 7, 11, 12, 58, 59, 31, 33, 30]. Nonetheless, the large discrepancies between the rat model and human data clearly indicate the limit of knowledge that one can gain from a rat model, and that a better understanding of the relationship between urinary and medullary P O2 in the human kidney might benefit from a model of the human kidney.…”

Section: Discussionmentioning

confidence: 99%

Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat

Sgouralis

Evans

2016

Math Med Biol

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Renal hypoxia could result from a mismatch in renal oxygen supply and demand, particularly in the renal medulla. Medullary hypoxic damage is believed to give rise to acute kidney injury, which is a prevalent complication of cardiac surgery performed on cardiopulmonary bypass (CPB). To determine the mechanisms that could lead to medullary hypoxia during CPB in the rat kidney, we developed a mathematical model which incorporates (i) autoregulation of renal blood flow and glomerular filtration rate, (ii) detailed oxygen transport and utilization in the renal medulla, and (iii) oxygen transport along the ureter. Within the outer medulla, the lowest interstitial tissue PO2, which is an indicator of renal hypoxia, is predicted near the thick ascending limbs. Interstitial tissue PO2 exhibits a general decrease along the inner medullary axis, but urine PO2 increases significantly along the ureter. Thus, bladder urinary PO2 is predicted to be substantially higher than medullary PO2. The model is used to identify the phase of cardiac surgery performed on CPB that is associated with the highest risk for hypoxic kidney injury. Simulation results indicate that the outer medulla’s vulnerability to hypoxic injury depends, in part, on the extent to which medullary blood flow is autoregulated. With imperfect medullary blood flow autoregulation, the model predicts that the rewarming phase of CPB, in which medullary blood flow is low but medullary oxygen consumption remains high, is the phase in which the kidney is most likely to suffer hypoxic injury.

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Section: Discussionmentioning

confidence: 99%

Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat

Sgouralis

Evans

2016

Math Med Biol

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“…The reason why dapagliflozin treatment decreases urea excretion in diabetic rats is also not clear. A small number of studies have shown that SGLT2 inhibition induced SGLT1 up-regulation and activation[26, 27]. Some data indicate that SGLT1 may be an alternative channel for urea uptake[28].…”

Section: Discussionmentioning

confidence: 99%

Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

Chen

LaRocque

Efe

et al. 2016

The American Journal of the Medical Sciences

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Aim This study evaluates the effect of dapagliflozin, a SGLT2 inhibitor, on fluid/electrolyte balance and its effect on urea transporter-A1 (UT-A1), aquaporin-2 (AQP2) and Na-K-2Cl cotransporter (NKCC2) protein abundance in diabetic rats. Methods Diabetes mellitus was induced by injection of streptozotocin into the tail vein. Serum Na+, K+, Cl− concentration, urine Na+, K+, Cl− excretion, blood glucose, urine glucose excretion, urine volume, urine osmolality and urine urea excretion were analyzed after the administration of dapagliflozin. UT-A1, AQP2 and NKCC2 proteins were detected by western blot. Results Dapagliflozin treatment decreased blood glucose by 38% at day 7 and 47% at day 14 and increased the urinary glucose excretion rate compared with the untreated diabetic animals. Increased 24-h urine volume, decreased urine osmolality and hyponatremia, hypokalemia and hypochloremia observed in diabetic rats were attenuated by dapagliflozin treatment. Western analysis showed that UT-A1, AQP2 and NKCC2 proteins are up-regulated in DM rats over control rats; dapagliflozin treatment results in a further increase in IM tip UT-A1 protein abundance by 42% at day 7 and 46% at day 14, but it did not affect the DM-induced up-regulation of AQP2 and NKCC2 proteins. Conclusion Dapagliflozin treatment augmented the compensatory changes in medullary transport proteins in DM. These changes will tend to conserve solute and water even with persistent glycosuria. Therefore, diabetic rats treated with dapagliflozin have a mild osmotic diuresis compared to non-diabetic animals, but this does not result in an electrolyte disorder or significant volume depletion.

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“…We assume that interstitial concentrations vary linearly between the cortico-medullary junction and the OM-IM boundary and between the OM-IM boundary and the papillary tip. The interstitial fluid in the cortex is taken to be homogeneous, with one exception: following the approach of Weinstein (54,55), we assume that there is a NH 3 /NH 4 ϩ concentration gradient in the cortex. The total interstitial concentration of ammonia (NH 3 ϩ NH 4 ϩ ) is taken to increase from 0.2 mM in the upper cortex to 1.0 mM at the corticomedullary boundary.…”

Section: Other Model Assumptionsmentioning

confidence: 99%

Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

Layton

Vallon

Edwards

2016

American Journal of Physiology-Renal Physiology

127

152

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Diabetes increases the reabsorption of Na(+) (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption [Formula: see text] along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising [Formula: see text] by 5-12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments.

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A mathematical model of the rat nephron: glucose transport

Cited by 39 publications

References 43 publications

Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat

Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat

Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

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