Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

Layton, Anita T.; Vallon, Volker; Edwards, Aurélie

doi:10.1152/ajprenal.00007.2015

Cited by 126 publications

(146 citation statements)

References 57 publications

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“…Mathematical modeling indicates that the largest contributor to the increase in renal Na + reabsorption and QO2 in diabetes is the augmented GFR, which increases tubular sodium and glucose loads (42). According to the tubular hypothesis, GFR increase in the diabetic kidney is due to primary proximal tubular hyperreabsorption caused by increased SGLT activity and tubular growth (43).…”

Section: Increased Oxygen Consumption In the Diabetic Kidneymentioning

confidence: 99%

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

2016

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Type 2 diabetes mellitus causes excessive morbidity and premature cardiovascular (CV) mortality. Although tight glycemic control improves microvascular complications, its effects on macrovascular complications are unclear. The recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV and all-cause mortality and hospitalization for heart failure without any effects on classic atherothrombotic events is puzzling. More puzzling is that the curves for heart failure hospitalization, renal outcomes, and CV mortality begin to separate widely within 3 months and are maintained for >3 years. Modest improvements in glycemic, lipid, or blood pressure control unlikely contributed significantly to the beneficial cardiorenal outcomes within 3 months. Other known effects of SGLT2 inhibitors on visceral adiposity, vascular endothelium, natriuresis, and neurohormonal mechanisms are also unlikely major contributors to the CV/renal benefits. We postulate that the cardiorenal benefits of empagliflozin are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation, which are energy inefficient in the setting of the type 2 diabetic heart and kidney, toward an energy-efficient super fuel like ketone bodies, which improve myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute translate into large differences in efficiency, and improved cardiorenal outcomes over weeks to months continue to be sustained. Well-planned physiologic and imaging studies need to be done to characterize fuel energeticsbased mechanisms for the CV/renal benefits.Type 2 diabetes mellitus (T2DM) is a chronic debilitating disease that leads to excessive morbidity and premature cardiovascular (CV) mortality worldwide. Although studies have documented the benefits of optimal glycemic control on microvascular complications, the effect of tight glycemic control on macrovascular complications is unclear (1). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, tight glycemic control increased CV and all-cause mortality (2). Glitazones and saxagliptin (a dipeptidyl peptidase 4 inhibitor) increase the risk of hospitalization for heart failure (HF) (3,4). In this context, the recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV/all-cause mortality and hospitalization for HF is a game changer, and if replicated, it may lead to a

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Section: Increased Oxygen Consumption In the Diabetic Kidneymentioning

confidence: 99%

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

2016

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“…The model is based on previously applied models of the proximal tubule (26), TAL (12), distal convoluted tubule (DCT) (11), connecting tubule (CNT) (11), and collecting duct (CD) (53), together with a new, simple model of the descending limb (see below). Each nephron segment is represented as a rigid tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type (Fig.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…The proximal convoluted tubule (PCT, also referred to as the S1-S2 segments) expresses the high-capacity, low-affinity transporters SGLT2 and GLUT2, whereas the proximal straight tubule (PST, also referred to as the S3 segment) expresses the lowcapacity, high-affinity transporters SGLT1 and GLUT1. As in our previous study (26), the fluxes of glucose and Na ϩ across SGLT2 cotransporters are calculated based on the sodiumalanine cotransporter model (20), which posits a simultaneous mechanism for the transport of Na ϩ and glucose, such that the fluxes are given by· Table 3). The diagram displays only the main Na ϩ , K ϩ , and Cl Ϫ transporters.…”

Section: Sodium-glucose Cotransport In the Proximal Tubulementioning

confidence: 99%

“…, which is given by F(⌿ lum Ϫ ⌿ cyt )/(RT), denotes the nondimensional apical membrane potential difference; ⌿ lum and ⌿ cyt represent the electric potential in the lumen and cytosol, respectively, R is the ideal gas constant, F is the Faraday constant, and T is the temperature. As in our previous study (26), the fluxes of glucose and Na ϩ across SGLT1 are computed using a six-state kinetic model (13,37), which assumes a Na ϩ :glucose stoichiometry of 2:1. Glucose fluxes across GLUT are determined based on the Maki and Keiser model (27) …”

Section: Sodium-glucose Cotransport In the Proximal Tubulementioning

confidence: 99%

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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

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129

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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“…As the triggering signals of the two mechanisms are largely independent but interrelated through blood flow which influences both local pressure and filtration rate, highly non-trivial interactions among the two mechanisms are developed [4,7,26,77]. A potential extension of the present afferent arteriole model would be to include a model of nephron transport (e.g., [78][79][80][81][82]) and tubuloglomerular feedback (e.g., [7,[83][84][85]). That would result in an integrative model of renal hemodynamics regulation that can be used for studying the interactions between the myogenic and tubuloglomerular feedback mechanisms in the context of renal autoregulation and for investigating changes in renal hemodynamics in pathophysiological conditions, especially under circumstances (e.g., hypertension and diabetes mellitus) involving complex multilevel responses [5].…”

Section: Discussionmentioning

confidence: 99%

A Multicellular Vascular Model of the Renal Myogenic Response

2018

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Abstract:The myogenic response is a key autoregulatory mechanism in the mammalian kidney. Triggered by blood pressure perturbations, it is well established that the myogenic response is initiated in the renal afferent arteriole and mediated by alterations in muscle tone and vascular diameter that counterbalance hemodynamic perturbations. The entire process involves several subcellular, cellular, and vascular mechanisms whose interactions remain poorly understood. Here, we model and investigate the myogenic response of a multicellular segment of an afferent arteriole. Extending existing work, we focus on providing an accurate-but still computationally tractable-representation of the coupling among the involved levels. For individual muscle cells, we include detailed Ca 2+ signaling, transmembrane transport of ions, kinetics of myosin light chain phosphorylation, and contraction mechanics. Intercellular interactions are mediated by gap junctions between muscle or endothelial cells. Additional interactions are mediated by hemodynamics. Simulations of time-independent pressure changes reveal regular vasoresponses throughout the model segment and stabilization of a physiological range of blood pressures (80-180 mmHg) in agreement with other modeling and experimental studies that assess steady autoregulation. Simulations of time-dependent perturbations reveal irregular vasoresponses and complex dynamics that may contribute to the complexity of dynamic autoregulation observed in vivo. The ability of the developed model to represent the myogenic response in a multiscale and realistic fashion, under feasible computational load, suggests that it can be incorporated as a key component into larger models of integrated renal hemodynamic regulation.

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Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition

Cited by 126 publications

References 57 publications

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

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

A Multicellular Vascular Model of the Renal Myogenic Response

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