Renal disease encompasses acute and chronic lesions altering renal physiological function. Chronic kidney disease (CKD) is characterized by an alteration of kidney structure and/or function lasting for more than 3 months (1). Acute kidney injury (AKI) is defined by a sudden increase in serum creatinine or decrease in urine output (2, 3). AKI is recognized as one of the main factors contributing to CKD progression (4, 5) and is associated with significant mortality (6). Although they represent two different diseases by definition, AKI and CKD share many common traits and are very much interrelated (5). Understanding the pathophysiology of both acute and chronic renal injury is mandatory to address the unmet medical need. Tubular cells are important players in AKI and in the progression of CKD. Metabolic modifications and mitochondrial dysfunctions of these cells are key to fibrosis development (7).

The kidney displays the second highest metabolic rate (>400 kcal/kg tissue/day) (8) after the heart. It uses ~7% of the total body daily energy despite its relatively low weight (9). The high energetic needs of the kidney are due on one hand to the transport and active reabsorption of nutrients and electrolytes in the tubules and on the other hand to the active secretion of unneeded compounds (10). Depending on the segment of the nephron, tubular cells use different substrates such as glucose, amino acids, fatty acids, or ketone bodies to produce energy through fatty acid oxidation (FAO) and glycolysis (11, 12). Glycolysis is the process that converts glucose into pyruvate through 10 enzymatic reactions; pyruvate is subsequently converted into acetyl-CoA. FAO is the breakdown of fatty acids at the mitochondrial level that also generates acetyl-CoA. Acetyl-CoA is then used as substrate for the tricarboxylic acid cycle (TCA) and the electron transport chain to produce adenosine triphosphate (ATP). The kidney is also able to perform gluconeogenesis (similarly to the liver), a metabolic pathway that produces glucose from non-hexose precursors. The kidney is therefore both an important consumer of energy and a producer of glucose and participates in systemic glucose metabolism (13).

Proximal tubular cells (PTCs) are the cells that produce and consume most of the energy in the kidney (14). Under physiological condition, their ability to generate ATP relies mostly on the oxidative phosphorylation of acetyl-CoA from FAO (12). Oxidative phosphorylation allows the production of energy through the transfer of electrons from nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) to oxygen, finally leading to ATP production. Besides, PTCs possess the ability to produce energy from a wide range of other substrates, including glutamine, lactate, pyruvate, acetate, citrate, or ketone bodies. PTCs are able to regulate glucose homeostasis by the de novo glucose production through gluconeogenesis but also by the reabsorption of large amounts of glucose, mostly via SGLT2 on the apical membrane of S1-2 segments and in a lesser extent via SGLT1 in the S3 segment. After reabsorption, glucose is released in the blood by glucose transporters (GLUT) (15). However, PTCs are almost unable to use glucose as an energetic substrate, except for the S3 segment (12). This specificity is due to the close localization of the S3 segments to the outer medulla and hence to its strong exposure to changes in O₂ levels. The complete breakdown of fatty acids is depends on the presence of oxygen and S3 cells therefore have to rely on other energy sources than FAO in case of low oxygen supply (16). On the contrary, the cells in the more distal segments of the nephron display enhanced glycolytic capacity and progressively lose their capacity to perform gluconeogenesis and oxidative phosphorylation. Besides, they can use less varied substrates than the PTCs (10) (Figure 1). Finally, because of their passive blood filtration process glomerular, endothelial and mesangial cells display low rates of oxidative phosphorylation (17). They have a basic glycolytic metabolism, with the ability to perform either aerobic or anaerobic glycolysis, thus producing less energy but with greater efficiency when O₂ supply is low (18, 19). As a result, they are less sensitive to changes in O₂ levels than PTCs.

In this review, we will primarily focus on the altered metabolism of PTCs during renal disease. Although several metabolic pathways are interrelated, we here mainly discuss glucose metabolism modifications during kidney disease and its potential local and systemic consequences.

PTCs are the largest group of tubular cells and are at highest risk of being exposed to hypoxia and other types of injury (20). The importance of these cells in the pathophysiological process of AKI and CKD is now well-established and the specific influence of PTC metabolic alterations in the pathological processes of renal disease has received increasing attention. Among metabolic alterations, mitochondrial dysfunction (21–27) and FAO downregulation (21, 28–30) have been described and already been reviewed (31–36). We here describe in more details the modifications of glucose metabolism in PTCs that occurs during acute and chronic injuries.

Glycolysis is a 10 steps pathway that leads to the production of pyruvate (Figure 2). The first step is catalyzed by hexokinases, which phosphorylates glucose into glucose-6-phosphate (G6P). Glucose phosphate isomerase rearranges G6P into fructose 6-phosphate. Fructose can also be phosphorylated and enter the pathway at this stage (37). Fructose 6-phosphate is then transformed in fructose 1,6-bisphosphate by phosphofructokinase 1, an ATP-dependent reaction and a key regulatory point of the pathway (38, 39). After several steps leading to phosphoenolpyruvate, the pyruvate kinase catalyzes the last reaction, which is also a regulatory point (40). Depending on O₂ availability, pyruvate is transported into the mitochondria to enter the TCA cycle or in the absence of oxygen, pyruvate is converted into lactate (41). The regulating enzymes of glycolysis are hexokinases, phosphofructokinases, and pyruvate kinases. These three enzymes are activated by the AMP/ADP ratio. Phosphofructokinase is additionally activated by fructose-2,6-bisphosphate and pyruvate kinase by fructose-1,6-bisphosphate. Hexokinase is inhibited by glucose-6-phosphate, phosphofructokinase, ATP, and citrate. Likewise, pyruvate kinase is inhibited by ATP, acetyl-CoA, and alanine (42). Insulin, stimulation of glucose uptake and epinephrine enhance glycolysis (43, 44). Among negative regulators of the pathway are glucagon, cortisol and growth hormone (42, 45, 46).

Physiologically, in conditions of high oxygen supply, fatty acids are mainly taken up by PTCs and used for oxidative phosphorylation to generate ATP. However, AKI is usually associated with a decrease in oxygen supply or relative oxygen deficiency in PTCs. PTCs are hence forced to use glycolysis instead of FAO. This is well-described in different models of AKI, which have shown pyruvate depletion, glycolysis intermediates accumulation and glycolytic enzymes upregulation during this condition (27, 47–51) even at late stages post-reperfusion (27). In chronic disease, analysis of metabolomics and RNA sequencing data from human databases have demonstrated an upregulation of glycolysis, showing a specific metabolic pattern of CKD patients (52, 53). A similar shift toward glycolysis has been observed in obstructive mouse models, with an increased lactate to pyruvate ratio (54).

Gluconeogenesis is a major kidney metabolic pathway, specifically present in healthy PTCs that produces glucose from non-hexose substrates such as lactate, pyruvate, glycerol, or amino acids (55) (Figure 2). In the kidney, lactate is the main substrate of gluconeogenesis and accounts for around 50% of glucose production. It is followed by glutamine (20%) and glycerol (10%) (56, 57). The conversion of pyruvate into glucose is the central pathway of gluconeogenesis. For this, 10 enzymatic reactions are necessary, seven of which are reversible and three that are irreversible. Phosphoenolpyruvate carboxykinase 1 (PCK1) catalyzes the formation of phosphoenolpyruvate from oxaloacetate, fructose-1,6-bisphosphatase 1 (FBP1) catalyzes the hydrolysis of fructose 1,6-biphosphate to fructose 6-phosphate and Glucose 6-phosphatase catalyzes glucose 6-phosphate to D-glucose. Gluconeogenesis plays a crucial role in glycemic homeostasis (58). Indeed, during fasting, once glycogen stores becomes depleted, the body will increasingly rely on endogenous glucose production. Although the liver has for a long time been considered as the sole source of glucose production, the kidneys are responsible for 40% of de novo glucose production during the fasted state (13, 59, 60). Renal gluconeogenesis is positively regulated by stress hormones such as hydrocortisone, epinephrine, and norepinephrine (56, 57, 61, 62), which could be linked to a regulation of PCK/Pyruvate Carboxylase (PC) activity (63–65). Insulin on the other hand downregulates renal gluconeogenesis (66), which could be due to PCK1/G6Pc regulation through phosphorylation (66, 67) but also to the reduction of substrates availability (glycerol and glutamine) (68, 69) or their redirection to the oxidative pathways (13, 68). Gluconeogenesis is regulated by factors implicated in global metabolic regulation, such as peroxisome proliferator-activated receptor alpha (PPARα) (70), Forkhead Box O1(FOXO1) (71) and hepatocyte nuclear factor 4 alpha (HNF4α) but also by glucose levels, through the modification of the NAD⁺/NADH ratio which causes an indirect downregulation of PCK1 at mRNA level (66). Acidosis also seems to play a role, with the induction of PCK1 at the mRNA and enzymatic activity level (72, 73) and hence increased renal glucose production.

The regulation of gluconeogenesis during renal pathology was not well-studied until recently. In AKI, a downregulation of gluconeogenesis enzymes was shown in single-cell analysis of mouse AKI as well as in RNA sequencing data from post-transplant AKI patients (74). Alterations of lactate clearance and glucose production were observed using renal catheterism data and rodent experimental models. In a cohort of intensive care unit patients, alterations of metabolism were associated with mortality, underlying the importance of renal glucose metabolism at a systemic level. Overall, gluconeogenesis decreases during AKI and leads to systemic metabolic alterations. In CKD, our preliminary results show similar alterations of gluconeogenesis are observed in a stage specific manner.

Altogether, a metabolic switch from FAO and gluconeogenesis to glycolysis occurs in PTCs during AKI and CKD. To date, the exact cause of this metabolic switch remains unknown. Initially, the switch constitutes a protective mechanism allowing PTCs to maintain energy production in case of low oxygen supply: HIF activation indeed enhances glycolysis through the stimulation of several enzymes of the pathway (hexokinases, glyceraldehyde-3-phosphate dehydrogenase, enolases, phosphofructokinases) and through the activation of glucose transporters (GLUT1-3) (75–77). In later stages of renal disease, inflammation and TGFβ activation could also play an important role in the persistence of the metabolic switch (78, 79); the induction of glycolysis was reproduced by IL-β and c-myc signaling activation (32, 52). In addition, the expression of co-regulators of FAO and glycolysis such as HNF4α or estrogen-related receptor alpha (ESRRA) are modified during AKI (74). Although it is initially cytoprotective, the persistence of the switch may be maladaptive and is associated with a worse kidney prognosis (21, 80, 81). In the second part of this review, we will detail the potential consequences of such metabolic modifications.

The transition from gluconeogenesis and FAO to glycolysis can have positive or detrimental consequences. Impaired glucose metabolism has been closely linked with mitochondrial dysfunction and a global decrease in energy production (27). The metabolic shift could also directly impact epithelial-mesenchymal transition (EMT) and fibrogenesis and therefore enhance CKD progression. Finally, the accumulation of metabolic precursors may influence renal disease (Figure 3).

Besides its potential effects on the outcome of kidney disease, modifying renal glucose metabolism has a systemic impact. Alteration of tubular cell metabolism may also imply release of new metabolites that can affect unexpected systemic functions (Figure 3).

Metabolic adaptation of renal cells during acute or sustained injury is a complex mechanism. The metabolic switch from fatty acid oxidation and gluconeogenesis toward glycolysis is part of a cytoprotective stress mechanism. However, persistence of this metabolic profile is associated with fibrogenesis. Glucose metabolism impairment could have a broad impact, ranging from local to systemic consequences. Interestingly, renal glucose metabolism is amenable to therapeutic interventions.

AF reviewed the literature, drafted the manuscript, and drew the figures. TV reviewed the literature, edited the manuscript, and drew the figures. HA reviewed the literature and edited the manuscript. DL edited the manuscript and the figures. SS designed and supervised the project, edited the manuscript and the figures. All authors contributed to the article and approved the submitted version.

AF was the recipient of a grant from the Swiss National Science Foundation (SNSF 323530_191224) and from the Carlos et Elsie de Reuter Founding. SS was supported by grants from the Swiss National Science Foundation (SNSF PP00P3-187186/1), Jules Thorn Foundation and NCCR Kidney.ch.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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