The role of metabolic reprogramming in tubular epithelial cells during the progression of acute kidney injury

Abstract

Acute kidney injury (AKI) is one of the most common clinical syndromes. AKI is associated with significant morbidity and subsequent chronic kidney disease (CKD) development. Thus, it is urgent to develop a strategy to hinder AKI progression. Renal tubules are responsible for the reabsorption and secretion of various solutes and the damage to this part of the nephron is a key mediator of AKI. As we know, many common renal insults primarily target the highly metabolically active proximal tubular cells (PTCs). PTCs are the most energy-demanding cells in the kidney. The ATP that they use is mostly produced in their mitochondria by fatty acid β-oxidation (FAO). But, when PTCs face various biological stresses, FAO will shut down for a time that outlives injury. Recent studies have suggested that surviving PTCs can adapt to FAO disruption by increasing glycolysis when facing metabolic constraints, although PTCs do not perform glycolysis in a normal physiological state. Enhanced glycolysis in a short period compensates for impaired energy production and exerts partial renal-protective effects, but its long-term effect on renal function and AKI progression is not promising. Deranged FAO and enhanced glycolysis may contribute to the AKI to CKD transition through different molecular biological mechanisms. In this review, we concentrate on the recent pathological findings of AKI with regards to the metabolic reprogramming in PTCs, confirming that targeting metabolic reprogramming represents a potentially effective therapeutic strategy for the progression of AKI.

Introduction

Acute kidney injury (AKI) is a clinical syndrome caused by multiple etiologies. The renal function declines rapidly once AKI occurs. There are around 13.3 million people suffered from AKI annually in the world. Among them, 85% come from developing countries, including Asia, Africa, Latin America and China. In addition to the high mortality, the long-term prognosis of AKI is poor and usually presented with chronic kidney disease (CKD) or end-stage renal disease (ESRD). Risk of CKD and ESRD is eightfold and threefold higher respectively in AKI patients when compared with those without AKI [1]. However, less effective clinical interventions are being applied. Thus, it is of vital necessity to further explore the underlying mechanisms of AKI [2].

The kidney is one of the most energy-demanding organs in the human body. It needs large amounts of ATP to remove waste products from the blood, reabsorb nutrients, regulate electrolyte and fluid balance, and maintain acid–base balance [3]. Different regions of the kidney have different requirements for ATP, depending on the type of cell. Among them, podocytes, endothelial cells and mesangial cells mainly use glucose for their energy supply, while renal tubular cells mainly use free fatty acids, glutamine, pyruvate, citrate and lactate as substrates for fuel supply through aerobic respiration [4]. It is well known that many common renal insults, for example, ischemia or toxic injury, primarily target the tubular epithelial cells especially the highly metabolically active proximal tubular segment [5, 6]. Proximal tubular cells (PTCs) are the most energy-demanding cells, which efficiently use fatty acid β-oxidation (FAO) as a fuel source. FAO yields more ATP per substrate molecule than glucose oxidation and is therefore advantageous given the high energy demand of these cells. Like most highly metabolic cells, when PTCs face various biological stresses, such as transient hypoxia or drug toxicity, FAO will shut down for a while that outlives injury [7, 8]. Deranged FAO in PTCs leads to impaired energy production, lipid accumulation, tubular cell injury, and fibrosis [9]. Interestingly, recent studies suggest that surviving PTCs during AKI can adapt to FAO defects by increasing glycolysis when facing those metabolic constraints, although PTCs cannot use glucose as a fuel in a normal physiological state [4, 10, 11]. Enhanced glycolysis in a short period compensates for impaired energy production and exerts partial renal-protective effects, but its long-term effect on renal function and AKI to CKD progression is not promising. These adverse effects may be related to a key glycolytic enzyme pyruvate kinase M2 (PKM2) [10, 11] or the final product of glycolysis lactate [12]. This review summarizes the pathophysiology of metabolic reprogramming in PTCs after AKI and the progression from AKI to CKD in recent years. We will highlight the promising effects of targeting metabolic reprogramming which represents a potentially effective therapeutic strategy for the progression of AKI.

Energy metabolism in PTCs under physiological conditions

It has been found that most kidney tubule segments are mitochondrial-enriched and depend almost exclusively on FAO and ensuing mitochondrial oxidative phosphorylation (OXPHOS) as their sole energy source to meet their functional needs [13]. FAO mainly occurs in mitochondria and includes a repeated series of reactions that lead to the conversion of FAs to acetyl-CoA. FAs are chiefly taken up by PTCs through CD36. CD36, scavenger receptor B2, is a multifunctional FA transporter that primarily mediates lipid uptake of cells [14]. Otherwise, FAs from the deacylation of cellular phospholipids are regulated by phospholipase A2 (PLA2). Whatever their origin is, FAs are first activated in the cytosol and produce long-chain acyl-CoA under the action of long-chain acyl-CoA synthetase. Due to the absence of an acyl-CoA transporter in the mitochondrial inner membrane, the long-chain acyl-CoA is transferred to the shuttle molecule carnitine for translocation into the matrix [15]. Carnitine palmitoyltransferase (CPT) 1 is located in the inner mitochondrial membrane and is the rate-limiting enzyme of the carnitine shuttle. CPT catalyzes the synthesis of long-chain lipid acyl CoA and carnitine into lipoyl carnitine. Then lipoyl carnitine passes from the inner membrane to the matrix of mitochondria with the assistance of carnitine-lipoyl carnitine translocase which translocates equimolecular carnitine out of mitochondria. After entering the mitochondrial matrix, CPT2 helps lipoyl carnitine transform to lipoyl CoA again and releases carnitine in the inner membrane of mitochondria. Finally, lipoyl CoA that inside mitochondria is fully oxidized by the fatty acid oxidase system, and produces a large number of acetyl CoA, flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH) for energy transformation [16]. A large amount of FADH2 and NADH later enter the oxidative respiratory chain to make ATP via oxidative phosphorylation. During oxidative phosphorylation, complex I and complex II transfer electrons from FADH2 and NADH to ubiquinone which passes electrons to complex III. Later, complex III transfers electrons to cytochrome c, gives electrons via complex IV to oxygen and produces H₂O. During these processes, the passage of electrons from the matrix to the intermembrane space of mitochondria gives rise to a membrane electronic potential difference, which drives the conversion from ADP to ATP through ATP synthase [16]. Although FAO enables producing quantities of ATP in a short time, it requires an ample supply of oxygen as well. This makes PTCs more sensitive than other cell types to changes in oxygen levels. Indeed, a lower oxygen supply can lead to impaired oxidation reactions and ATP synthesis which in turn can trigger kidney injury. This may partly explain why the kidney exhibits imbalance of energy supply and is extremely prone to ischemic injuries, such as blood loss, surgery or trauma [17].

Moreover, the kidney also has an important role in gluconeogenesis and PTCs are the only kidney cell type that is capable of de novo synthesis of glucose, mainly using lactate as a precursor {recent reviews: [18, 19]}. This process is regulated by insulin and cellular glucose levels, and acidosis and stress hormones as well [20]. However, PTCs from S₁ and S₂ segments of the PT are unable to use glucose as a fuel because they are short of sufficient hexokinase (HK) activity. Different from the upstream S₁ and S₂, S₃ segments have slightly higher HK activity and can produce ATP from glucose [21]. Another reason to prevent glycolysis from producing ATP is that PTs harbor a high glucose concentration gradient from their luminal (urinary filtrate) to the basal (blood) side for glucose reabsorption. Hence, using glucose to derive energy could be toxic, especially under conditions of metabolic imbalance such as in diabetes [22]. Generally, PTCs metabolize a wide range of substrates but have little capacity for glycolysis.

Mitochondrial dysfunction in PTCs onset of AKI

Mitochondrion is a cellular “energy factory” which provides sources of energy to maintain basic cellular behavior, repair and regeneration. FAO, tricarboxylic acid cycle (TCA) and oxidative phosphorylation exert their roles mainly in mitochondria. Mitochondrial dysfunction including abnormal mitochondrial biosynthesis, kinetics and oxidative phosphorylation eventually leads to impaired mitochondrial energy production [9]. Effective mitochondria function is essential for sustaining the energic supply of PTCs. However, in the case of AKI, it is found that mitochondria in PTCs show various degrees of swelling and fracture. Mitochondrial damage greatly contributes to the imbalance of energy metabolism in PTCs and is considered as one of the essential causes of cell apoptosis and necrosis of PTCs when AKI is present [23, 24] (Fig. 1).

Fig. 1.

Changes in mitochondria result in tubular impairment in AKI. A healthy proximal tubule consists of an intact brush border with tight junctions and contains a network of mitochondria to maintain its function. When a kidney is injured, mitochondria react directly and leads to impaired mitochondrial function and an injured proximal tubule. In the early stages of acute kidney injury (AKI), production of ATP is decreased, accompanied by a reduced level of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC⁃1α) and SIRT3. Harmonious interaction between fusion and fission of mitochondria plays an essential role and maintains mitochondrial homeostasis. Fusion of mitochondria is mediated by mitofusin 1 and 2 (MFN1 and MFN2), the outer mitochondrial membrane fusion protein and optic atrophy 1 (OPA1), the inner mitochondrial membrane fusion protein together. Besides, dynamin-related protein 1 (DRP1), a mitochondrial fission protein translocates into the mitochondria and binds with mitochondrial fission 1 (FIS1) to induce mitochondrial fragmentation. Taken together, these events trigger activation and accumulation of DRP1 and FIS1, thus promoting mitochondrial fragmentation and inducing cell death eventually. Cell death induced by mitochondrial dysfunction in injured proximal tubules triggers nuclei loss and tight junctions, and disrupts cellular brush borders

Interfered mitochondrial biosynthesis

Up to now, several critical regulators related to mitochondrial biosynthesis have been identified, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), and nuclear respiratory factors 1 and 2 (NRF1 and NRF2) [25]. PGC⁃1α is a major regulatory molecule of mitochondrial biosynthesis [26]. Dysfunctional mitochondria stimulate PGC⁃1α expression to foster biosynthesis of new mitochondria and to stabilize the structure, function and number of mitochondria, which in turn compensates for the need of increased energy supply [27]. Kidney health is especially reliant on PGC-1α. Under normal physiological conditions, PGC⁃1α is highly expressed in PTCs [28]. But the mRNA and protein expression of PGC⁃1α reduced obviously in a mouse model of sepsis-induced AKI. Reduced mitochondrial number and ATP production negatively correlated with the severity of AKI. The knockdown of PGC⁃1α in PTCs exacerbated renal injury and disease progression [29]. Oppositely, overexpressing PGC-1α restored the reduced mitochondria number and ATP production caused by oxidant exposure in primary cultures of PTCs, and accelerated recovery of mitochondrial and cellular functions [30]. In addition, in ischemia/reperfusion (I/R)-induced AKI mouse model, PGC⁃1α downregulated significantly as well [31]. Meanwhile, the overexpression of PGC-1α in PTCs reduced mortality and attenuated accumulation of renal lipid, which further demonstrated that the disturbance of mitochondrial biosynthesis in PTCs may be involved in AKI progression [31, 32].

Disturbed mitochondrial dynamics in PTCs

Mitochondria is one of the highly dynamic organelles inside cells, which strongly relies on constant division and fusion to maintain a reticular structure, stabilize quantity and quality, and finally adapt to different energy demands. Mitochondrial dynamics are regulated by a variety of proteins, including dynamin-related protein 1 (DRPl), mitochondrial fission protein 1 (FIS1), mitochondrial fusion protein 1/2 (MFNl/2) and optic atrophy protein (OPA1) [33]. Recent studies have demonstrated that abnormal mitochondrial dynamics in PTCs lead to impaired energy metabolism during the development of AKI [3]. Brook et al. demonstrated a striking morphological change of mitochondria in experimental models of renal I/R and cisplatin-induced nephrotoxicity [34]. They found that in an I/R mouse model, brief reperfusion after 30 min of renal ischemia caused approximately 30–40% mitochondrial breakage in PTCs; besides, this rapid mitochondrial breakage in PTCs was also observed after cisplatin treatment in vitro. The results from the studies on the underlying mechanism showed that when AKI occurs, DRP1 is activated by dephosphorylation and rapidly translocates to mitochondria, thereby promoting mitochondrial fission. On the contrary, Mdivi-1, an inhibitor of DRP1, can attenuate renal injury by inhibiting mitochondrial fracture. On the other hand, OPA1 is repressed by proteolysis, leading to dysregulation of mitochondrial fusion. The disruption of fission and fusion together leads to mitochondrial breakage [34, 35]. Moreover, Gall et al. observed that MFN2 deficiency in PTCs caused mitochondrial fragmentation and exacerbated cell injury by promoting Bax-mediated mitochondrial outer membrane injury and apoptosis [36]. In addition to the above, another important regulatory mechanism is worth mentioning here. Sirtuins (SIRT) is a class of highly conserved nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases. It is found that SIRT3 highly expressed in PTCs and widely distributed in mitochondria. It has been reported that SIRT3 plays an ultimate role in regulating mitochondrial dynamics and energy metabolism [37]. In 2015, Morigi et al. reported that cisplatin-reduced SIRT3 in cultured human PTCs resulting in mitochondrial fragmentation, whereas restoration of SIRT3 improved cisplatin-induced mitochondrial dysfunction [38]. Likewise, Wang et al. found that SIRT3 maintained mitochondrial homeostasis against I/R injury by enhancing OPA1-triggered fusion of mitochondrion [39]. These studies suggest that enhancing SIRT3 to improve mitochondrial dynamics may improve outcomes of renal injury.

Metabolic reprogramming in PTCs during AKI

As previously mentioned, PTs, as the main site of renal reabsorption, require a large amount of energy to maintain normal function. Under physiological conditions, PTCs preferentially use FAO in the mitochondria to produce energy but hardly use glucose [40]. However, when AKI occurs due to various stressors including ischemia and hypoxia, drug toxicity, and sepsis, mitochondrial respiratory function in PTCs is impaired and the glycolysis pathway is enhanced to provide sufficient energy to maintain cell viability [10, 41] (Fig. 2).

Fig. 2.

Energetic metabolic reprogramming of proximal tubular epithelial cells during AKI. Kidneys prefer fatty acids (FAs) for energy production. CD36 facilitates the uptake of FAs in proximal tubular epithelial cells. FAs mainly stored in global triglyceride pool to produce ATP. In cytosol, FAs are activated to acyl-CoA and transported to mitochondria by the carnitine shuttle. In the outer mitochondrial membrane, carnitine palmitoyl-transferase 1 (CPT-1) catalyzes transesterification from acyl-CoA to acylcarnitine. However, CPT1 decreased significantly during AKI and reduced ATP production. Intracellular FAs accumulation positively regulates expression of enzymes in FAO transcriptionally via activating peroxisome proliferator activated receptor-alpha (PPARα). But in AKI, level of PPAR-α, and its DNA binding activity decreases which inhibits transcription of FAO related enzymes. In the meanwhile, hexokinase (HK) is activated to increase glucose-6-phosphate dehydrogenase activity when AKI is induced. Besides, activated hypoxia-induced factor-1 (HIF-1α) induces expression of M2 isoform of pyruvate kinase (PKM2) and slows down the conversion of phosphoenol pyruvate to pyruvate. Moreover, HIF-1α promotes the transformation of pyruvate into lactate and inhibits the transformation from pyruvate into acetyl-CoA, thus blocking its entry into the Krebs cycle

Impaired FAO

FAO is the preferred energy source of the kidney and is inhibited during AKI [42]. Peroxisome proliferator-activated receptor alpha (PPARα) belongs to a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARα plays an essential role in regulating cellular differentiation, development, and metabolism (carbohydrate, lipid, protein). PPARα is predominantly expressed in metabolically active cells, such as PTCs [43]. PPARα increases the transcription of genes encoding FAO enzymes, and also acts upstream by stimulating cellular FA uptake through the modulation of the FA translocase CD36 [44, 45]. More and more evidence showed that PPARα plays an important role in the regulation of FA homeostasis. In I/R and cisplatin-induced AKI, the expression of PPARα in PTCs is reduced, thus leading to an impaired long-chain FAO and cell necrosis [46–48]. However, treating PTCs with PPARα agonists reverses those above impairment [49]. In addition, the intranuclear level of PPARα and its transcriptional activity is maintained by cyclophilin d blockage in PTCs. Blocking cyclophilin d inhibits cisplatin-induced FAO damage and intracellular lipid deposition [50]. Besides, a decline in the activity of CPT1 in PTCs has been seen resulting in reduced uptake of FAs in the mitochondrial matrix and, hence, reduces FAO during I/R injury. By treating the kidney with CPT1 activator C75, the FAO increases with a consequent improvement of renal morphology [51]. Moreover, it has also been observed that renal FAO-related enzymes are inhibited to some extent during I/R stages [52]. In a word, these conclusions suggest that both transport of FAs from the cytoplasm to the mitochondrial matrix and mitochondrial oxidation of FAs are impaired in PTCs during AKI.

Enhanced glycolysis

Enhanced glycolysis combined with mitochondrial dysfunction is a hall-mark of various AKI aetiologies, including I/R injury, sepsis and toxic drugs. Lan et al. found that during early and late reperfusion after I/R, kidneys exhibited increased HK activity and pyruvate content and lactate, which are indicators of glycolysis [10]. Additionally, they observed that normally regenerating PTs as well as those undergoing atrophy showed inhibitory phosphorylation of pyruvate dehydrogenase and increased glycolytic enzyme expression. Smith et al. assessed changes in renal cortical glycolytic metabolism in sepsis-induced AKI mouse model. They also observed a specific and rapid increase in HK activity (∼twofold) after lipopolysaccharides (LPS) exposure, which was associated with increased glucose-6-phosphate dehydrogenase activity [53]. Another study showed that treating human renal proximal tubular epithelial cells (HK2) with antiviral drugs led to dysregulated mitochondria, increased anaerobic glycolytic capacity, decreased cellular oxygen consumption (OCR) and enhanced extracellular acidification rate (ECAR) [54]. Mechanically, it is well known that under hypoxic conditions, hypoxia-inducible factor 1α (HIF-1α) is involved in the conversion from predominantly mitochondrial respiration towards increased glycolysis by upregulating the expression of glycolytic enzymes [55]. Conde et al. revealed that short interfering RNA (siRNA) against HIF-1α exacerbated renal I/R injury [56]. A later study further proved that inhibiting HIF-1α by siRNA during reperfusion had deleterious effects on kidney injury and renal fibrosis [57]. Additionally, Lovisa et al. found that renal capillary endothelial cells underwent Twist- and Snail-mediated endothelial-to-mesenchymal transition (EndMT) leading to persistent vascular damage and renal tissue hypoxia. This process drives renal fibrosis by affecting metabolic reprogramming through altered Myc signaling in PTCs [58, 59]. EndMT is critically linked to metabolic reprogramming of PTCs such as switching from FAO to glucose utilization. In the future, it will be interesting to further elucidate the role of metabolic programming of endothelial and epithelial cells and whether it can be therapeutically targeted.

Relationship between metabolic reprogramming and AKI progression

AKI is a contributing factor in the development and progression of chronic kidney disease (CKD). Fibrosis is the final common pathway and the histological manifestation of CKD [60]. Some molecular mechanisms of AKI to CKD transition have been uncovered, including nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction and epigenetic changes [61]. In addition to mechanisms linked above, the relationship between cellular metabolic reprogramming and AKI to CKD transition has become a hot research topic in recent years [62].

As described above, PTCs depend mainly on FAO in mitochondria to provide ATP. FAO will temporarily shut down when AKI occurs. If FAO does not recover properly after insult, lipid accumulation and/or reduction of FAO possibly participate in the mesenchymal reprograming of PTCs, increasing the risk of developing CKD from even transient AKI [63]. Kang et al. reported that palmitic acid (PA)-stimulated PTCs treated with Etomoxir (CPT-1 inhibitor) displayed higher cell death, dedifferentiation and intracellular lipid accumulation [64]. Additionally, they found these PTCs underwent a fibrotic phenotype transition, with the expression of more mesenchymal genes, such as α-SMA, vimentin, col1a1 and col3a1. In line with this, another study reported that PTCs treated with PA showed a decrease of FAO enzymatic activity, and an increase in lipid accumulation and epithelial-to-mesenchymal transition (EMT) [65]. In addition, higher intracellular lipid accumulation may impact PTCs independently from the FAO pathway [14]. Lipid accumulation was due mainly to an imbalance in FAs’ utilization and supply. High levels of albumin-bound long-chain saturated FAs promoted the progression of renal tubular damage and interstitial fibrosis through activation of pro-inflammatory pathways, including tumor necrosis factor-alpha (TNF-α), CC motif chemokine 2 and interleukin (IL)-6, and increased the production of reactive oxygen stress (ROS) [66, 67]. Furthermore, albumin-bound FAs have been reported to activate PPAR-δ, leading to cytochrome c release and caspase 3 activation [68]. Last, ablation of the FA transport protein CD36 has been demonstrated to ameliorate inflammation and tubulointerstitial fibrosis by reducing the expression of inflammatory cytokines and chemokines, suggesting CD36 could be a potential therapeutic target for renal injury [69, 70]. Hou et al. also observed in their recently published paper that overexpression of CD36 promoted NLRP3 inflammasome activation and IL-1β secretion in high glucose-induced PTCs, which suppressed mitochondrial FAO and stimulated mitochondrial ROS production [71]. Overall, lipid accumulation probably contributes to AKI to CKD transition, either through the activation of an apoptotic signal or pro-inflammatory pathways. These results indicate that early restoring FAO in PTCs might be a new strategy to prevent AKI and even hinder renal fibrosis.

As previously mentioned, PTCs rely on enhanced glycolysis for more energy supply when FAO shuts down. However, interestingly, Lan et al. found that the shift from fatty acid oxidative phosphorylation to glycolytic metabolism in PTCs undergoing I/R injury played a key role in the development of renal tubular atrophy and AKI to CKD transition [10]. It seems that increased glycolysis may be a double-edged sword for the prognosis of AKI. Some researchers propose that the effects of upregulated key enzymes in the glycolytic pathway, such as PKM2 and metabolic end product lactate need more attention. Lan’s team found that PKM2 co-localized with vimentin, a marker on atrophic PTCs after I/R injury, whereas PKM2 was not expressed in well-differentiated PTCs [10]. Moreover, in the unilateral ureteral obstruction (UUO) mouse model, the elevated expression of PKM2 in renal tubular epithelial cells influenced the differentiation and proliferation of podocytes and promoted renal interstitial fibrosis [11]. The above findings suggest that PKM2 not only participates in the glycolysis pathway, but also may aggravate the renal tubular injury and interstitial fibrosis. Furthermore, Palsson-McDermott et al. demonstrated that the expression of PKM2 increased upon LPS treatment in activated macrophages and this was attributed to the accumulation of succinate [72]. High levels of succinate were found to promote the production of IL-1β [73] through PKM2-mediated activation of HIF-1α [72]. In an experimental model of endotoxemia, increased PKM2 in macrophages contributed to the release of high mobility group box 1 (HMGB1) [74]. Recently, Li et al. found that increased phosphorylated PKM2 in endothelial cells activated the STAT3 and NF-κB pathways, thereby inducing ICAM-1 expression, which eventually led to renal inflammation [75]. Combined with the above findings, it can be hypothesized that PKM2 may have a close relationship with the induction of inflammatory response. Then, is it possible that AKI-induced release of large amounts of proinflammatory cytokines such as IL-1β and HMGB1 is associated with an increase of PKM2 in PTCs? If the answer is yes, perhaps we can partially explain why enhanced glycolysis drives the conversion of AKI to CKD. However, the effect and mechanism of this phenomenon on renal function and pathology, and whether it can be a target for disease intervention, still need to be investigated more thoroughly.

For the past few years, lactate as an end product of the glycolysis pathway, has been found to play an important role in tumor formation and progression. It has been demonstrated that lactate can promote tumor cell proliferation, immune escape and inflammatory response [76]. Besides, lactate enhances metabolic reprogramming by inducing HIF-1α stabilization, thus creating a positive feedback loop that leads to intracellular lactate accumulation and exacerbates mitochondrial dysfunction [77]. In the folic acid-induced AKI mouse model, Shen et al. found that increased glycolysis in PTCs following acute injury was imperative for fibroblast activation and proliferation. Lactate generated from injured tubules was taken up by interstitial fibroblasts in the later stages of AKI, which induced fibroblast activation and proliferation. Early inhibition of lactate production in tubules by glycolytic inhibitors suppressed fibroblast activation [12]. Additionally, fibroblast activation by lactate has also been proved to play a role in wound healing, pulmonary fibrosis and tumor growth [78–81]. Moderate intracellular lactate promoted fibroblast proliferation and extracellular matrix (ECM) production through stimulating TGF-β, activating oxidative stress and cell cycle regulation [82, 83]. Moreover, another research revealed that metabolic reprogramming in PTCs during UUO-induced AKI affected the number and function of podocytes and aggravated renal interstitial fibrosis [11]. Treating podocytes with lactate inhibited cell proliferation and differentiation, suggesting that lactate may damage podocytes. However, the effects of lactate on glomeruli, tubules and interstitium may not be limited to interstitial fibrosis and podocyte injury, and further studies are needed to explore its role and mechanism.

Potential treatments for restoring deranged FAO

Renal diseases have been recognized to be a huge global burden and mitochondrial dysfunction is closely associated with various acute and chronic kidney injuries. As mentioned above, disorders of mitochondrial FAO are capable of triggering kidney injury and further inducing fibrotic responses. Therefore, the protection of mitochondria represents a potential drug target. Several new mitochondrial-targeted approaches are currently under development. Growing evidence suggests that increased PPARα and PGC-1α are two potential mechanisms that may account for recovered FAO [30, 49]. In a murine model, it was demonstrated that the pretreatment with a low dose of PPARα agonist clofibrate prevented acute tubular injuries, which may be associated with FAO maintenance, decrease of intracellular lipid accumulation, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NF-κB activation [84]. Another type of fibrate, fenofibrate exhibited a similar effect to clofibrate; that is, it attenuated I/R-induced renal dysfunction through the modulation of endothelial nitric oxide synthase (eNOS) expression [85]. Moreover, fenofibrate reduced kidney injury and fibrosis by suppressing NF-κB and TGF-β signaling pathways in UUO and diabetic nephropathy models [64, 86, 87]. Although fenofibrate is effective in protecting kidneys, its use in clinical trials for AKI patients requires caution because of its ability to raise serum creatinine [88]. Furthermore, Gu et al. observed that gastrin protected the kidney against hypertensive injury by inducing cholecystokinin receptor B (CCKBR) nuclear translocation and increasing PPARα gene transcription [89]. Hao et al. found that formononetin attenuated the inflammation, oxidative stress and apoptosis caused by cisplatin‑induced AKI through activation of the PPARα/NRF2 pathway [90]. These compounds may be new potential drugs for AKI patients. In addition to PPARα, the stimulation of PGC-1α pathway could also provide a possible intervention strategy [91]. The PPAR-γ agonist, pioglitazone, activated PGC-1α and ameliorated age-related renal injury [92]. Formoterol, a β2-adrenergic receptor agonist, stimulated PGC-1a expression and mitochondrial respiration in PTCs [93]. The administration of formoterol after ischemic AKI accelerated the recovery of mitochondrial and renal function via upregulation of PGC-1α [94].

Another strategy to rescue ATP levels after AKI must be mentioned here, namely the mitochondria-targeting compound SS-31. Szeto et al. found that the treatment with SS-31 after renal ischemia injury preserved mitochondrial homeostasis and down-regulated inflammatory cytokines, eventually alleviating glomerulosclerosis and interstitial fibrosis [95]. In line with this study, Liu et al. demonstrated that SS-31 not only protected mitochondrial cristae in PTCs during ischemia, but also accelerated ATP recovery upon reperfusion [96]. Apart from SS-31, a recent study has reported another mitochondrial-targeted peptide SS-20. SS-20 pretreatment obviously inhibited mitochondrial swelling and ameliorated the coupling efficiency of mitochondrial respiration, which significantly improved renal fibrosis after I/R-induced AKI [97]. These findings reveal the role of mitochondrial dysfunction in the pathogenesis of AKI and the potential for the use of mitochondrial-targeted therapy in the process.

Conclusion

In summary, impaired mitochondria greatly mediate the development of AKI and later renal fibrosis. Demonstrated by disturbed mitochondrial biosynthesis and kinetics, impaired oxidative phosphorylation and FAO deficiency, energy metabolism in PTCs is interfered. During these processes, PTCs undergo metabolic reprogramming to compensate for the energy supply and anti-oxidative stress in a short period; however, a long-term activation of metabolic reprogramming promotes the development of AKI. A number of studies focused on identifying the relationship between metabolic reprogramming and renal proximal tubular injury. It has been indicated that the upregulation of key enzymes of glycolysis and their end products suggest a compensatory form of energy supplementation in proximal tubules after AKI. Although the effects and underlying mechanisms of metabolic reprogramming have been fully elucidated in oncological diseases, the downstream effects of metabolic reprogramming on proximal renal tubular injury still remain poorly identified. This article reviews recent studies on the molecular mechanisms of metabolic reprogramming in PTCs during the progression of AKI. These data suggest that metabolic reprogramming is not only one of the main pathophysiological mechanisms underlying AKI progression, but also a major determinant of the fibrotic outcome, as targeted deranged FAO reverses the pro-inflammatory and pro-fibrotic phenotypes observed in a long-term evolution. Given the existed evidence that metabolic reprogramming triggers cell damage and inflammatory and fibrotic responses, early restoring mitochondrial β-oxidation and/or promoting mitochondrial biosynthesis in PTCs may be more effective than contraposing a single downstream event when developing strategies to effectively block AKI progression. With a better understanding of metabolic reprogramming in PTCs and its physiological functions, we expect that these findings will translate into future therapeutic strategies to alleviate kidney injury and delay the progression of CKD.

Authors’ contribution

ZL, SL and XL all reviewed the literature and wrote the manuscript. All authors have read and approved the final manuscript.

Funding

Not applicable.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.