| | |  | | NEWSLETTER ::: NO. 21 ::: DEC 2020 | | ION TRANSPORT ACTIVITIY AND TUBULAR METABOLISM ARE LINKED IN KIDNEY DISEASE | | Transport and metabolism are closely linked in the kidney. The movement of large amounts of water and solutes by tubular epithelial cells generates a huge demand for ATP. |  | | In chronic kidney disease (CKD), the increased oxygen consumption by remnant nephrons may lead to activation of hypoxia sensing mechanisms. This in turn could cause downregulation of normal metabolic processes, like fatty acid metabolism and gluconeogenesis, whilst activating pro-inflammatory and pro-fibrotic pathways. Understanding the exact nature of these changes could reveal new targets for intervention to slow the progression of CKD.
The major function of the kidney tubule is to reabsorb vast amounts of water and solutes filtered by glomeruli, to maintain body homeostasis. This is an energy-expensive process, and as a result, tubular epithelial cells have to produce a lot of ATP, the molecular currency of energy within most biological systems. The majority of this then consumed by the enzyme Na⁺/K⁺-ATPase, also known as the “Na-pump”, which is highly expressed along the basolateral membrane of tubular cells. The Na-pump uses one ATP molecule to actively extrude three intracellular sodium ions, while simultaneously taking in two extracellular potassium ions. The resulting electrochemical gradients are then leveraged to drive the activity of various co-transporters, antiporters and ion channels. In this manner, the active transcellular transport of sodium is directly coupled to that of many other solutes, including chloride, phosphate, glucose, and amino acids. Moreover, by generating transepithelial potential differences and concentration gradients, it is also essential for promoting paracellular ion and fluid reabsorption.
In total, active ion transport by renal epithelial cells consumes about 3 kg of ATP per day in humans. Intense cellular metabolism is needed to meet this demand, and the kidney ranks second only to the heart for mitochondrial density and oxygen consumption. However, each specific tubular segment relies to a greater or lesser extent on different metabolic pathways. For example, proximal tubule cells – which perform the bulk of solute transport – mainly depend on oxidative metabolism of fatty acids, whilst glycolysis is more active in distal segments. The efficiency of tubular sodium transport is an index of the overall metabolic cost of solute reabsorption. It is calculated as the ratio between oxygen consumption rate and the number of sodium ions transported per unit of time. Efficiency levels progressively decrease from the proximal to the distal tubules, reflecting the fact that beta oxidation of fatty acids provides the biggest yield of ATP per molecule of fuel. It is also worth mentioning that proximal tubular cells use other reabsorbed metabolites (such as lactate, glycerol and some amino acids) to make glucose, by a process is called gluconeogenesis. In fact, the kidneys contribute about one third of the body’s glucose production, something which is often overlooked.
In both acute kidney injury (AKI) and CKD, major changes in tubular metabolism have been found to occur. For example, when acutely damaged by insults like ischemia, proximal tubular cells undergo a dramatic shift from fatty acid oxidation to glycolysis, presumably as a protective mechanism to maintain ATP levels and minimize oxidative stress when the normal oxygen supply is compromised. Crucially, in our recent studies in patients with AKI, we have also demonstrated that proximal tubules lose the ability to produce glucose. This leads to major systemic consequences, such as hypoglycemia, which might in turn explain the high levels of morbidity and mortality seen in such patients (Legouis et al., Nature Metabolism). Such metabolic changes in the proximal tubule are accompanied by a downregulation of master regulators of mitochondrial biogenesis and fatty acid oxidation, such as PGC1. Moreover, substantial decreases in the critical metabolic co-factor NAD+ have been documented and NAD+ replenishment in animals restores mitochondrial function and ATP generation, leading to better outcomes. Clinical trials of NAD supplementation are now underway to see if these exciting findings can translate to humans.
Following an acute insult to the kidney, patients are often left with fewer remaining nephrons, which have to increase their workload accordingly to compensate. Some individuals then develop a syndrome of progressive loss of kidney function, known as CKD. This is characterized histologically by increasing interstitial immune cell infiltration and fibrosis, which gradually destroys and replaces the tubules. Recent studies suggest that fatty acid metabolism also becomes downregulated in proximal tubules in CKD, and that the resulting lipid overload stimulates pro-inflammatory and pro-fibrotic signaling, thus mechanistically linking these events. What actually causes this apparently adverse metabolic switch remains unclear, but it is likely to represent a chain reaction of events, with rises in active electrolyte transport increasing the rate of oxygen consumption, potentially leading to a decrease in tissue oxygen content and the triggering of hypoxia sensors. Indeed, we have recently shown that stimulating sodium transport in the kidney tubule directly increases oxygen usage and activates hypoxia inducible factor (HIF), a master metabolic regulator that co-ordinates a myriad of adaptive responses. We are now exploring whether this activation of the HIF pathway may drive the shift away from oxidative metabolism of fatty acids to glycolysis in proximal tubules, and if so, whether this could thus represent an upstream target for intervention to prevent fibrosis.
In summary, our past and recent works are aiming to explore the potential role of metabolic switches in kidney tubular cells as a causative event in the pathogenesis of progressive renal failure. These studies could help to find promising therapeutic targets in the race to halt the progression of CKD.
| | Eric Feraille and Sophie de Seigneux are are members of the NCCR Kidney.CH.
Eric Feraille is an Associate Professor of Fundamental Medicine at the Department of Cell Physiology and Metabolism of the University of Geneva. He was one among the initial team members who successfully built the NCCR Kidney.CH along with Prof. François Verrey.
Sophie de Seigneux is an Assistant Professor of Nephrology at the Department of Internal Medicine of the University Hospital of Geneva. She is recipient of Swiss National Foundation professorship. She has also served as co-leader of the NCCR’s “Work Package: Oxygen” for almost 6 years as of now.
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| | | | Kidney - Control of Homeostasis | | is a Swiss research initiative, headquartered at University of Zurich, which brings together leading specialists in experimental and clinical nephrology and physiology from the universities of Bern, Fribourg, Geneva, Lausanne, and Zurich, and corresponding university hospitals. |
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