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Renal Tubular Metabolism Reviewed in Health and Disease nutrients Review Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease Leslie S. Gewin 1,2,3 1 Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA; [email protected] 2 Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, TN 37212, USA 3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37212, USA Abstract: The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression. Keywords: proximal tubule; acute kidney injury; chronic kidney disease; fatty acid oxidation; kidney injury; kidney metabolism Citation: Gewin, L.S. Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease. Nutrients 2021, 1. Introduction 13, 1580. https://doi.org/10.3390/ The kidney receives 25% of the cardiac output and filters approximately 180 L of nu13051580 water daily, while only excreting 1 to 2 L. In addition, over 1.6 kg of salt is filtered but only 3–20 g is eliminated, and significant energy is expended to conserve such a large fraction of Academic Editor: Emily Sonestedt water and salt in addition to glucose and other filtered solutes [1]. The human kidney is a complex organ with approximately 1 million nephrons, with each comprising glomerulus Received: 10 April 2021 and subsequent tubular segments. The tubular compartment of the kidney consists of the Accepted: 30 April 2021 proximal tubule (with S1 segment closest to the glomerulus, S2, and S3), loop of Henle, Published: 9 May 2021 distal convoluted tubule, and the collecting duct. The renal tubules are responsible for conserving 99% of the water and solutes in the glomerular filtrate, as well as maintaining Publisher’s Note: MDPI stays neutral acid/base balance. The metabolic needs and substrate preference (e.g., glucose and fatty with regard to jurisdictional claims in acids) vary depending upon the specific tubule segment. published maps and institutional affil- iations. The kidney can be injured acutely by ischemia, toxins, drugs, and infection or can be chronically impaired by diabetes, hypertension, glomerulonephritides, or severe acute kidney injuries. The renal tubules, particularly the proximal tubules, are vulnerable to both acute kidney (AKI) and chronic kidney disease (CKD). There is strong evidence that renal tubular metabolism is altered in both AKI and CKD. Emerging evidence suggests that Copyright: © 2021 by the author. correcting some of these metabolic changes may attenuate injury or improve recovery, but Licensee MDPI, Basel, Switzerland. questions persist about which metabolic perturbations are adaptive versus maladaptive. This article is an open access article This review will discuss what is known about metabolism in the healthy kidney tubules, distributed under the terms and conditions of the Creative Commons how tubular metabolism changes in kidney injury, and the unanswered questions regarding Attribution (CC BY) license (https:// how metabolic changes may affect tubular repair and tubulointerstitial fibrosis progression, creativecommons.org/licenses/by/ the hallmark of CKD. 4.0/). Nutrients 2021, 13, 1580. https://doi.org/10.3390/nu13051580 https://www.mdpi.com/journal/nutrients NutrientsNutrients2021 2021,,13 13,, 1580x FOR PEER REVIEW 2 of2 of16 15 2. Metabolism in in the the Healthy Healthy Kidney Kidney 2.1. Fatty Acid Acid Oxidation Oxidation The primary cells cells responsible responsible for for the the large large reabsorptive reabsorptive capacity capacity of of the the kidney kidney are are proximal tubules tubules which which reclaim reclaim about about 70% 70% of filtered of filtered solutes solutes and andwater. water. To facilitate To facilitate this massivethis massive amount amount of water of waterand solute and solutetransport, transport, a high anumber high number of ATP- ofconsuming ATP-consuming trans- porterstransporters are needed. are needed. Abundant Abundant mitochondria mitochondria are present are in present proximal in tubules proximal to tubulesgenerate to thegenerate necessary the necessary ATP. Similar ATP. to Similar the metabolically to the metabolically active cardiomyocyte, active cardiomyocyte, the proximal the proximal tubule reliestubule on relies fatty on acid fatty oxidation acid oxidation (FAO) because (FAO) because this fuel this source fuel provides source provides 106 ATP 106 units ATP com- units paredcompared to 36 tofrom 36 fromglucose glucose metabolism metabolism (Figure (Figure 1A) [2].1A) Most [ 2 ].of Mostthe outer of the kidney, outer or kidney, cortex, or iscortex, comp isosed composed of proximal of proximal tubules. tubules.Consistent Consistent with this withlarge thismass large of proximal mass of tubules, proximal earlytubules, studies early showed studies that showed two- thatthirds two-thirds of oxygen of consumption oxygen consumption in the human in the kidney human comes kidney fromcomes fatty from acid fatty oxidation acid oxidation [3]. [3]. A B Figure 1. Metabolism in theFigure uninjured 1. Metabolism nephron and in the proximal uninjured tubule. nephron (A) The and proximal proximal tubule tubule. segment (A) The has proximal gluconeogenic tubule capacity and preferentiallysegment uses fatty has acid gluconeogenic oxidation to capacity generate and ATP. preferentially By contrast, uses the fatty distal acid tubules oxidation do not to generate have gluco- ATP. neogenic potential but are betterBy contrast, equipped the dist to generateal tubules ATP do not through have gluconeogenic glycolysis. (B) potential Schematic but of are metabolism better equipped within to the gen- erate ATP through glycolysis. (B) Schematic of metabolism within the proximal tubule showing proximal tubule showing that glucose is taken up on the apical side by SGLT1/2 transporters and released on the basal that glucose is taken up on the apical side by SGLT1/2 transporters and released on the basal side side through GLUT1/2. Fattythrough acids GLUT1/2. (FA) cross Fatty the plasma acids (FA) membrane cross the through plasma CD36,membrane fatty through acid binding CD36, proteins fatty acid (FABP), binding and fatty acid transport proteinsproteins (FATP), (FABP), convert and fatty into acid acetyl-CoA transport and proteins are transported (FATP), convert into the into mitochondria acetyl-CoA throughand are trans- the carnitine shuttle involving theported carnitine into the palmityol-transferases mitochondria through CPT1a the carnitine and CPT2. shu Betattle oxidationinvolving of the fatty carnitine acyl-CoA palmityol produces-trans- acetyl-CoA which enters theferases TCA (tricarboxylicCPT1a and CPT2. acid) Beta cycle. oxidation Oxidation of fatty of acetyl-CoA acyl-CoA produces by the TCA acetyl produces-CoA which NADH enters which the enters the electron transportTCA chain (tricarboxylic (ETC) to generate acid) cycle. ATP. Oxidation Created with of acetyl BioRen-der.com.-CoA by the TCA produces NADH which enters the electron transport chain (ETC) to generate ATP. Created with BioRen-der.com. Fatty acids can be taken up by renal tubules primarily through the CD36 receptors expressedFatty onacids plasma can be membranes, taken up by but renal also tubules through primarily fatty acid through binding proteinsthe CD36 (FABPs) receptors and expressedfatty acid transporton plasma proteins membranes, (FATPs) but (Figure also through1B) [ 4– fatty7]. In acid addition, binding they proteins can be (FABPs) produced andthrough fatty fattyacid transport acid synthase proteins in the (FATPs) cytosol (Figure or by 1B) metabolism [4–7]. In addition, of phospholipids they can be through pro- phospholipaseduced through A2 fatty [2]. acid Long-chain synthase fatty in acidsthe cytosol (LCFA) or such by asmetabolism palmitate requireof phospholipids the carnitine throughshuttle for phospholipase transport into A2 mitochondria [2]. Long-chain where fatty oxidation acids (LCFA) and ATP such generation as palmitate occurs. require The thecarnitine carnitine shuttle shuttle consists for trans of carnitineport into palmitoyl-transferasemitochondria where oxidation 1 (CPT1), and located ATP generation on the outer occurs.mitochondrial The carnitine membrane, shuttle which consists converts of carnitine fatty acylpalmitoyl CoA into-transferase a long-chain 1 (CPT1), acylcarnitine, located onallowing the outer movement mitochondrial into the membrane, mitochondrial which matrix converts [8]. The fatty carnitine acyl CoA palmitoyltransferase-2 into a long-chain (CPT2)acylcarnitine, enzyme allowi thenng reconstitutes movement into acyl-CoA, the mitochondrial which undergoes matrixβ [-oxidation8]. The carnitine in the pal- mito- mitoyltransferasechondria.
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