Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis

Moss, Robert; Thomas, Sophie

doi:10.1152/ajprenal.00089.2013

Cited by 27 publications

(25 citation statements)

References 329 publications

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“…We should nevertheless acknowledge some of its limitations. We consider one representative nephron, without distinguishing between superficial and juxta-medullary nephrons, when in fact luminal concentrations at the mTAL inlet are predicted to vary significantly with the length of Henle's loop (33,42,54). Because the model does not take into consideration the complex architecture of the medulla and the role of vasa recta, it assumes fixed interstitial concentration gradients along the corticomedullary axis, following the approach of Weinstein (61); we did, however, abolish these gradients in the furosemide simulations.…”

Section: Discussionmentioning

confidence: 99%

Regulation of calcium reabsorption along the rat nephron: a modeling study

Edwards

2015

American Journal of Physiology-Renal Physiology

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We expanded a mathematical model of transepithelial transport along the rat nephron to include the transport of Ca(2+) and probe the impact of calcium-sensing mechanisms on Ca(2+) reabsorption. The model nephron extends from the medullary thick ascending limb (mTAL) to the inner medullary collecting duct (IMCD). Our model reproduces several experimental findings, such as measurements of luminal Ca(2+) concentrations in cortical tubules, and the effects of furosemide or deletion of the transient receptor potential channel vanilloid subtype 5 (TRPV5) on urinary Ca(2+) excretion. In vitro microperfusion of rat TAL has demonstrated that activation of the calcium-sensing receptor CaSR lowers the TAL permeability to Ca(2+), PCa (TAL) (Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P. J Clin Invest 122: 3355, 2012). Our results suggest that this regulatory mechanism significantly impacts renal Ca(2+) handling: when plasma Ca(2+) concentration ([Ca(2+)]) is raised by 10%, the CaSR-mediated reduction in PCa (TAL) per se is predicted to enhance urinary Ca(2+) excretion by ∼30%. If high [Ca(2+)] also induces renal outer medullary potassium (ROMK) inhibition, urinary Ca(2+) excretion is further raised. In vitro, increases in luminal [Ca(2+)] have been shown to activate H(+)-ATPase pumps in the outer medullary CD and to lower the water permeability of IMCD. Our model suggests that if these responses exhibit the sigmoidal dependence on luminal [Ca(2+)] that is characteristic of CaSR, then the impact of elevated Ca(2+) levels in the CD on urinary volume and pH remains limited. Finally, our model suggests that CaSR inhibitors could significantly reduce urinary Ca(2+) excretion in hypoparathyroidism, thereby reducing the risk of calcium stone formation.

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Section: Discussionmentioning

confidence: 99%

Regulation of calcium reabsorption along the rat nephron: a modeling study

Edwards

2015

American Journal of Physiology-Renal Physiology

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“…Typically, these models have just two nonelectrolyte solutes (NaCl and urea) and pay scant attention to transport in the cortex, or to TGF; they also omit hydrostatic pressure as a model variable. One notable exception is the recent work of Moss and coworkers (53,54), who have fashioned multinephron models focused on regulation of NaCl excretion, which has included a TGF signal from end-ascending Henle limb (AHL) lumen to afferent arteriolar resistance. There has been intense study of TGF in the steady-state regulation of SNGFR (51), and also in its capacity to affect the dynamics of tubule flow and pressure by introducing oscillatory behavior (43).…”

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confidence: 99%

A mathematical model of rat proximal tubule and loop of Henle

Weinstein

2015

American Journal of Physiology-Renal Physiology

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Weinstein AM. A mathematical model of rat proximal tubule and loop of Henle. Am J Physiol Renal Physiol 308: F1076 -F1097, 2015. First published February 18, 2015 doi:10.1152/ajprenal.00504.2014.-Proximal tubule and loop of Henle function are coupled, with proximal transport determining loop fluid composition, and loop transport modulating glomerular filtration via tubuloglomerular feedback (TGF). To examine this interaction, we begin with published models of the superficial rat proximal convoluted tubule (PCT; including flow-dependent transport in a compliant tubule), and the rat thick ascending Henle limb (AHL). Transport parameters for this PCT are scaled down to represent the proximal straight tubule (PST), which is connected to the thick AHL via a short descending limb. Transport parameters for superficial PCT and PST are scaled up for a juxtamedullary nephron, and connected to AHL via outer and inner medullary descending limbs, and inner medullary thin AHL. Medullary interstitial solute concentrations are specified. End-AHL hydrostatic pressure is determined by distal nephron flow resistance, and the TGF signal is represented as a linear function of end-AHL cytosolic Cl concentration. These two distal conditions required iterative solution of the model. Model calculations capture inner medullary countercurrent flux of urea, and also suggest the presence of an outer medullary countercurrent flux of ammonia, with reabsorption in AHL and secretion in PST. For a realistically strong TGF signal, there is the expected homeostatic impact on distal flows, and in addition, a homeostatic effect on proximal tubule pressure. The model glycosuria threshold is compatible with rat data, and predicted glucose excretion with selective 1Na ϩ :1glucose cotransporter (SGLT2) inhibition comports with observations in the mouse. Model calculations suggest that enhanced proximal tubule Na ϩ reabsorption during hyperglycemia is sufficient to activate TGF and contribute to diabetic hyperfiltration. glomerulotubular balance; tubuloglomerular feedback; ammonia; glucose; glomerular hyperfiltration REGULATION OF PROXIMAL TUBULE transport depends upon local signals (physical and hormonal), which can be examined in isolated tubule segments, feedback from more distal tubule segments, and the impact of the peritubular environment. At the local level, glomerulotubular balance (GTB) denotes the classic micropuncture observation that proximal reabsorption varies proportionally with changes in the single-nephron glomerular filtration rate (SNGFR). This observation has been rationalized as the effect of microvillous drag on the actin cytoskeleton, and ultimately on the membrane transporters (17,20). To the extent that proximal tubule transport is modulated by luminal flow velocity, both SNGFR and luminal hydrostatic pressure impact reabsorptive fluxes. The effect of SNGFR on tubule fluid velocity is clear; the effect of pressure relies on the fact that axial velocity is the ratio of volume flow to luminal cross section, so to the extent that t...

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“…Indeed, one could make the case that of all the various branches of biology and medicine, physiology has the longest shared involvement with mathematical methods. For example, in renal physiology they have been critical in our understanding of glomerular filtration, solute transport across the tubular epithelium, autoregulation of renal blood flow, water and electrolyte homeostasis and counter‐current exchange of solutes in the renal medulla and thus urinary concentrating mechanisms . And yet, it is still the norm that education of physiologists includes little to no mathematical and computational modelling.…”

Section: Introductionmentioning

confidence: 99%

Renal oxygenation: From data to insight

et al. 2020

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Computational models have made a major contribution to the field of physiology. As the complexity of our understanding of biological systems expands, the need for computational methods only increases. But collaboration between experimental physiologists and computational modellers (ie theoretical physiologists) is not easy. One of the major challenges is to break down the barriers created by differences in vocabulary and approach between the two disciplines. In this review, we have two major aims. Firstly, we wish to contribute to the effort to break down these barriers and so encourage more interdisciplinary collaboration. So, we begin with a “primer” on the ways in which computational models can help us understand physiology and pathophysiology. Second, we aim to provide an update of recent efforts in one specific area of physiology, renal oxygenation. This work is shedding new light on the causes and consequences of renal hypoxia. But as importantly, computational modelling is providing direction for experimental physiologists working in the field of renal oxygenation by: (a) generating new hypotheses that can be tested in experimental studies, (b) allowing experiments that are technically unfeasible to be simulated in silico, or variables that cannot be measured experimentally to be estimated, and (c) providing a means by which the quality of experimental data can be assessed. Critically, based on our experience, we strongly believe that experimental and theoretical physiology should not be seen as separate exercises. Rather, they should be integrated to permit an iterative process between modelling and experimentation.

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Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis

Cited by 27 publications

References 329 publications

Regulation of calcium reabsorption along the rat nephron: a modeling study

Regulation of calcium reabsorption along the rat nephron: a modeling study

A mathematical model of rat proximal tubule and loop of Henle

Renal oxygenation: From data to insight

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