Renal Metabolism: Integrated Responses

Klahr, Saulo; Hamm, L. Lee; Hammerman, Marc R.; Mandel, Lazaro J.

doi:10.1002/cphy.cp080249

Cited by 12 publications

(27 citation statements)

References 413 publications

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“…Additionally, SNR was sufficient at 1.5 mm isotropic resolution from the heart to visualize uptake of lactate and pyruvate. Within the kidney, the biodistribution of each compound correlated with previous metabolic studies, with an infusion of either pyruvate or lactate resulting in stronger signal from the cortex and renal pelvis compared to the medulla [58,62]. In normal kidney function, especially after infusion, both lactate and pyruvate are readily metabolized, with reduction of pyruvate to lactate and oxidation of lactate to pyruvate, as well as conversion of lactate to glucose via gluconeogenesis and conversion to amino acids.…”

Section: Discussionmentioning

confidence: 58%

“…The presence of monocarboxylate transporters (MCTs) in red blood cells indicate each compound can be transported into and out of the cells [55–57] and would subsequently not be hindered in free movement about the vasculature or within different kidney compartments [58]. Furthermore, paramagnetic effects arising from certain oxidation states of hemoglobin may also have a significant relaxation effect on molecules that are transported into RBCs.…”

Section: Discussionmentioning

confidence: 99%

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Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

Milshteyn

Morze

Reed

et al. 2017

Magnetic Resonance Imaging

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The goal of this project was to develop and apply techniques for T2 mapping and 3D high resolution (1.5 mm isotropic; 0.003 cm3) 13C imaging of hyperpolarized (HP) probes [1-13C]lactate, [1-13C]pyruvate, [2-13C]pyruvate, and [13C,15N2]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5 mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T2 mapping experiments yielded measurements of T2 values of greater than 1 s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2-13C]pyruvate which was ~730 ms and ~320 ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1-13C]lactate, [1-13C]pyruvate, and [2-13C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003 cm3) spatial and 2 s temporal resolution in vivo utilizing HP 13C substrates by exploiting their long T2 values. This 1.5 mm isotropic resolution is comparable to 1H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

Milshteyn

Morze

Reed

et al. 2017

Magnetic Resonance Imaging

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“…Early studies estimated that the costs were 0.36 calories/mEq Na + in the proximal tubule, 1.4 calories/mEq Na + in the thick ascending limb (TAL), 2.7 calories/mEq Na + in the distal connecting tubule and 4.6 calories/mEq Na + in the collecting duct . Later estimates of segmental ratios have been somewhat less varied, with ratios of 1 : 2 : 6 for the proximal : TAL : distal tubule . There are at least two examples whereby an increase in Qo 2 and a reduction in metabolic efficiency could be explained.…”

Section: Variability In Metabolic Efficiency During Tubular Reabsorptionmentioning

confidence: 99%

Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension

Hansell

Welch

Blantz

et al. 2013

Clin Exp Pharma Physio

233

251

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SUMMARY The high renal oxygen (O2) demand is associated primarily with tubular O2 consumption (QO2) necessary for solute reabsorption. Increasing O2 delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension.The metabolic efficiency for solute transport (QO2/TNa) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na+ transporters, different levels of oxidative stress and segmental tubular dysfunction.Sustained hyperglycaemia results in increased kidney QO2, partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased QO2 is not matched by a similar increase in O2 delivery.Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O2 cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function.Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O2 metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.

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“…Inhibiting SGLT2 lowers the proximal tubule uptake of not only glucose but Na ϩ as well, thereby shifting glucose and Na ϩ reabsorption to downstream nephron segments, including the S3 segment of the proximal tubule and the thick ascending limb (TAL) in the vulnerable OM. Furthermore, the efficiency of Na ϩ transport (namely, the number of Na ϩ moles reabsorbed per O 2 moles consumed) changes along the nephron, with the early proximal tubule being more efficient than the distal segments (23). Finally, SGLT2 inhibitors have also been approved in diabetic patients with impairment of kidney function [estimated glomerular filtration rate (eGFR) Ͼ45 ml/min].…”

mentioning

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

126

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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Renal Metabolism: Integrated Responses

Abstract: The sections in this article are: Methodological Considerations Coupling of Metabolism to Transport Oxidative vs. Glycolytic Metabolism in the Mammalian Kidney Stoichiometry of Transepithelial Na + Transport to QO 2 Transport as the Pacemaker of Respirati… Show more

Cited by 12 publications

References 413 publications

Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension

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

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