With glucose as the foundational fuel to generate ATP, carbohydrate catabolism is the predominant energy production mechanism in most renal cells except proximal tubular cells (Gewin, 2021). The catabolic pathways include the oxidative phosphorylation and citric acid cycle and the glycolysis pathway. The pentose phosphate pathway (PPP) is an alternative anabolism pathway from glycolysis, which is critical for NADPH synthesis and oxidative stress suppression.

Proteins undergo constant degradation and synthesis to sustain regular cellular functions. As the backbone of proteins, some amino acids are re-used during this protein turnover, while other extra amino acids undergo deamination. Their carbohydrate skeletons can either enter the citric acid cycle as substrates for energy production or be utilized to synthesis glucoses and fatty acids (Murray et al., 2012). The kidney plays a critical role in managing the amino acid reservoir for protein turnover by either absorbing or releasing specific amino acids such as glutamine, proline, serine, and cystine (Garibotto et al., 2010). It uptakes approximately 30% glutamine, 60% proline, 100% citrulline, 100% S-adenosylhomocysteine, and 90% cysteinylglycine from the bloodstream while releasing 100% of serine and cysteine, 50% arginine, 50% tyrosine, and 5%–20% lysine into the bloodstream. The nitrogen resultant from deamination will be converted into urea in the liver, which will be cleared out of the body by the kidney. Thus, the blood urea nitrogen level is an important index to monitor kidney function.

Among the twenty amino acids necessary for protein synthesis, nine are essential amino acids that cannot be synthesized by mammalian cells and must be acquired through diet (Murray et al., 2012). In recent years, the importance of maintaining a balance in the metabolism of branched-chain amino acids (BCAAs)—which include the three essential amino acids, namely, leucine, valine, and isoleucine—and aromatic amino acids (AAAs) (such as phenylalanine, tryptophan, tyrosine, and histidine, with three of them being essential) has gained attention in kidney injury and repair as emerging research studies show that their deficiency can cause malnutrition and progression of kidney diseases (Piret et al., 2021a; Barba et al., 2021; Mahbub et al., 2021; Shan et al., 2023). However, the specific roles and functions of these amino acids remain largely unexplored.

During AKI, the renal tubular cells, especially the proximal tubular cells, suffer from severe mitochondrial damage, associated with the loss of some major enzymes for mitochondrial bioenergetics (Jin et al., 2021). Furthermore, the renal vascular impairment, resulting from the endothelial dysfunction, adversely affects the oxygen delivery efficiency and, consequently, the mitochondrial function (Zuk and Bonventre, 2016). Thus, the energy production via fatty acid β-oxidation, the citric acid cycle, and oxidative phosphorylation is significantly suppressed. Given that the proximal tubule is the major renal compartment with high-energy production demand from mitochondria, in AKI resulting from various injurious factors, the accumulation of lipid droplets in the kidney has been commonly observed (Iwaki et al., 2019; Jang et al., 2020b; Bugarski et al., 2021; Xu et al., 2022; Yang et al., 2023b; Chen et al., 2023; Wang et al., 2023). Therefore, promoting mitochondrial biogenesis has been considered a major therapeutic strategy for AKI treatment (Clark and Parikh, 2020; Pabla and Bajwa, 2022).

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the gene expression related to lipid metabolism and are crucial in regulating mitochondrial biogenesis (Gao and Gu, 2022). The activation of PPARs promotes fatty acid oxidation, enhancing the mitochondrial bioenergy production. The function of various PPAR isoforms has been extensively investigated in AKI. In ischemic AKI, the overexpression of PPARα has been shown to protect mice from renal injury (Li et al., 2009). In addition, PPARα prevents sepsis-induced AKI by promoting fatty acid metabolism, which in turn helps suppress inflammation (Iwaki et al., 2019). Both Krüppel-like factor 15 and ERK1/2 have been reported to regulate the transcription of PPARα (Collier et al., 2016; Piret et al., 2021b). In cisplatin-induced AKI, PPARα translocates from the nucleus to mitochondria, binding to cyclophilin D, which further suppresses its transcription activity and reduces fatty acid metabolism (Jang et al., 2020a). Another isoform PPARγ shows similar fatty acid metabolism regulation function, and its agonists have been reported to exert protective effects in experimental AKI models (Doi et al., 2007; Reel et al., 2013; Zhang et al., 2016; Chen et al., 2017; Singh et al., 2019; Liu et al., 2020; Sharma and Patial, 2022). Furthermore, PPARG coactivator 1 alpha (PGC1α) is a co-activator of PPAR isoforms and a critical regulator in mitochondrial biogenesis (Lynch et al., 2018). PGC1α is suppressed in AKI (Portilla et al., 2002; Tran et al., 2011) and its suppression or deficiency worsens the renal injury, while its induction in renal tubular cells ameliorates ischemic AKI (Tran et al., 2011; Ruiz-Andres et al., 2016; Tran et al., 2016; Fontecha-Barriuso et al., 2019). Despite the central role of the PPAR/PGC1α pathway in AKI, a recent clinical study of the PPARδ agonist ASP1128 did not show significant renal beneficial effects on reducing AKI incidence or severity after major cardiac surgery as expected (van Till et al., 2023). Overall, their therapeutic potential and effectiveness in clinical settings may vary, indicating a need for further development and research of new activating chemicals.

Since the depletion of functional mitochondria is a major pathological event in AKI, in recent years, the transplantation of mitochondria to scavenge the renal cells has been examined in AKI therapy (Doulamis et al., 2020; Jabbari et al., 2020; Pabla and Bajwa, 2022; Rossi et al., 2023). Initial studies by two independent research groups have demonstrated that mitochondrial delivery can attenuate ischemic AKI in both rat and swine models (Doulamis et al., 2020; Jabbari et al., 2020; Rossi et al., 2023). No significant safety issue has been detected by mitochondrial transplantation (Doulamis et al., 2020). However, there are still challenges to be addressed. Ensuring the viability of the transplanted mitochondria remains a significant concern, as their functionality is crucial for the therapeutic benefit. Additionally, the efficacy of mitochondrial transplantation in AKI scenarios other than I/R is yet to be established.

Notably, hypoxia, another key pathological condition in AKI, limits the mitochondrial bioenergetics even in the presence of functional mitochondria. Paradoxically, excessive oxygen consumption by mitochondria may further aggravate renal hypoxia. Thus, it raises a question whether the kidney can be rescued simply by increasing mitochondrial bioenergetics. Kidney oxygen consumption is directly proportional to the glomerular filtration rate and sodium reabsorption (Redfors et al., 2010). Zhou (2023) highlights an alternative strategy for AKI treatment: reducing renal oxygen consumption by inhibiting sodium reabsorption in renal tubular cells. While this strategy has shown promise in animal models, its clinical effectiveness remains controversial. Thus, it underscores further investigation to elucidate how to maintain a balance of renal oxygen delivery, mitochondrial function, and oxygen consumption during AKI therapy.

Although the total glycolysis level is suppressed in AKI, the mitochondrial dysfunction, especially in proximal tubules, shifts the balance of energy production toward glycolysis. However, the pathological function of glycolysis is complicated due to its close connection with other metabolic pathways (Figure 1), and its impact varies across different renal cells (renal tubular cells vs. inflammatory cells) and AKI conditions. Glycolysis can be beneficial as it helps prevent ATP depletion in renal tubular cells. Meanwhile, the suppression of glycolysis may shift the energy production to other pathways such as citric acid cycle and PPP. For instance, preconditioning treatments with meclizine, enarodustat, or AMPK activators, which enhance glycolysis in proximal tubular cells, have been shown to ameliorate ischemic AKI both in vitro and in vivo (Kishi et al., 2015; Lieberthal et al., 2016; Ito et al., 2020). Additionally, dichloroacetate treatment or knockout of its target pyruvate dehydrogenase kinase 4, which shifts metabolism from glycolysis to the citric acid cycle and oxidative phosphorylation, has been effective in protecting mice from cisplatin-induced nephropathy (Galgamuwa et al., 2016; Oh et al., 2017). In contrast, in AKI induced by sepsis, the inhibition of glycolysis with agents like 2-deoxyglucose has been observed to have a protective effect in mice (Ji et al., 2021; Tan et al., 2021). One possibility is that glycolysis may enhance inflammation to promote M1 macrophage polarization (Takakura and Zandi-Nejad, 2019; Yang et al., 2023c). Intriguingly, AMPK activation still shows protection in sepsis-induced AKI, possibly due to its role in enhancing oxidative phosphorylation as well (Jin et al., 2020). Furthermore, tubular-specific knockout of pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, has been reported to protect ischemic AKI by switching the metabolism to PPP (Zhou et al., 2019).

Disturbances in glycolysis during AKI result in altered levels of glycolytic metabolites, which can further influence renal injury and recovery. First, the acute loss of renal function leads to lactate accumulation, and the elevated serum lactate levels have been considered an index of AKI severity (Zhou et al., 2022b). One potential pathological role of lactate in AKI is to downregulate SIRT3 and p-AMPK, followed by autophagy inhibition (Tan et al., 2021). Furthermore, lactic acidosis has been considered to drive the development of CKD (Wesson et al., 2020). Pyruvate, the end product of anaerobic glycolysis and the initial metabolite for the citric acid cycle (Figure 1), decreases in the injured kidney (Zager et al., 2014). The renal protective effects of pyruvate have been identified in various AKI conditions, where it helps reduce oxidative stress and suppress inflammation (Salahudeen et al., 1991; Leelahavanichkul et al., 2008; Jun et al., 2018). In addition, fructose-1,6-bisphosphate, an intermediate metabolite in the glycolysis pathway (Figure 1), has been shown to mitigate kidney injury from I/R or cisplatin nephrotoxicity, although the underlying mechanism is not fully understood (Antunes et al., 2006; Azambuja et al., 2011).

Finally, some multifunctional enzymes in the glycolysis pathway, such as PKM2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), play crucial roles in regulating kidney injury through mechanisms beyond their primary metabolic functions. PKM2 is a rate-limiting enzyme to produce pyruvate in glycolysis. The specific knockout of PKM2 in renal tubular cells has been shown to protect mice from ischemic AKI and cisplatin-induced nephropathy (Zhou et al., 2019; Xie et al., 2023). While the exact mechanism through which PKM2 regulates ischemic AKI is not fully understood, its knockout seems to reduce oxidative stress and enhance PPP. In the kidneys injured by cisplatin, PKM2 is phosphorylated and translocates to mitochondria, leading to mitochondrial fragmentation and exacerbating tubular injury (Xie et al., 2023). PFKFB3, another enzyme in the glycolysis pathway, catalyzes the production of fructose 2,6-bisphosphate (F2,6P2), which in turn activates phosphofructokinase-1, a rate-limiting enzyme in glycolysis. PFKFB3 is significantly upregulated in the kidneys damaged by cisplatin, and its renal tubular-specific knockout or inhibition attenuates cisplatin-induced AKI (Wen et al., 2023). However, the detrimental role of PFKFB3 in kidney injury relies on the activation of CDK4 and the regulation of the cell cycle, rather than its metabolic activity. Considering the complexity of glycolysis-related metabolites and enzymes in different renal cells, much research is needed to examine the detailed function and mechanism of specific inhibitors or activators for glycolysis.

The activity of PPP in AKI varies depending on the initial insults of the kidney. In ischemic AKI, there is an increase in PPP-related gene expression 24 h post-injury (Scantlebery et al., 2021). In sepsis-induced AKI, the activity of glucose-6-phosphate dehydrogenase (G6PDH), a key enzyme in PPP, is significantly elevated (Smith et al., 2014). In the case of cisplatin-induced AKI, despite a decrease in intermediate metabolites, G6PDH activity is induced (Bushau-Sprinkle et al., 2020). PPP is unique in its ability to produce NADPH, which is critical for controlling oxidative stress and protection against kidney injury (Weng et al., 2018). The deficiency of G6PDH is directly associated with AKI in clinics (Owusu et al., 1972; Abdel Hakeem et al., 2016; Talwar et al., 2019). Furthermore, the induction of G6PDH or PPP activity has been shown to protect the kidneys from cisplatin- or I/R-induced AKI (Zhou et al., 2019; Bushau-Sprinkle et al., 2020). Notably, glucose can shuttle between PPP and glycolysis. Therefore, both the activation of hexokinase and the knockout of PKM2 have been reported to enhance PPP activity in the kidney (Smith et al., 2014; Zhou et al., 2019). However, whether the activation of PPP can regulate glycolysis is unclear. In addition, because PPP not only benefits the detoxification of oxidative stress but also provides basic metabolites for nucleotide synthesis, the detailed mechanism of PPP in AKI progression needs further exploration.

Various types of kidney injury lead to disturbances in amino acid metabolism, exhibiting different patterns depending on the nature of the injury. In ischemic AKI, there is a notable decrease in multiple amino acids, including glutamate, glutamine, tyrosine, proline, and methionine (Wei et al., 2014). Shan et al. (2023) have observed a significant reduction in plasma isoleucine levels following kidney I/R. In sepsis-induced AKI, a decrease in metabolites involved in BCAA metabolism has been detected (Standage et al., 2021). Following cisplatin treatment in mice, the urinary levels of alanine, leucine, and methionine have been significantly elevated, although the changes in their kidney levels have not been determined (Lim et al., 2023).

Our current understanding of the specific roles of individual amino acids in AKI is still evolving. Glycine has been extensively studied across various AKI conditions. Its administration has been shown to reduce free radical production and protect renal epithelial cells in both in vitro and in vivo models of ischemic AKI, as well as in lead- or cisplatin-induced nephrotoxicity (Heyman et al., 1991; Paller and Patten, 1992; Weinberg, 1992; Yin et al., 2002; Shafiekhani et al., 2019). However, this protective effect appears limited in milder injury conditions or chronic ischemia (Yin et al., 2002). Contrarily, Arora et al. (2014) have found that glycine administration can exacerbate ischemic AKI by activating the NMDA receptor. Moreover, glutamine supplementation has demonstrated universal protective effects in diverse AKI scenarios, including ischemic AKI, sepsis-induced AKI, cisplatin nephrotoxicity, and gentamycin-induced nephrotoxicity (Hu et al., 2012; Kim et al., 2015; Thomas et al., 2022; Zhan et al., 2022). L-Arginine deficiency has been identified in the kidney transplant recipients, and its supplementation protects rats from uranyl nitrate-induced AKI (Schramm et al., 2002). While BCAA metabolism has been reported to reduce aristolochic acid-induced kidney injury, potentially regulated by Krüppel-like factor 6 (Piret et al., 2021a), the mechanisms underlying these effects remain unclear. Overall, these findings underscore the complex and varied roles of amino acids in AKI, pointing to the need for much research to fully understand their functions and therapeutic potential in different AKI contexts.

While the overproduction of ketone bodies can lead to ketoacidosis in diabetic conditions, increasing the risk of AKI (Orban et al., 2014; Huang et al., 2022), the enhancement of plasma levels of ketone bodies within the normal range protects renal cells from AKI injury (Tajima et al., 2019; Rojas-Morales et al., 2022; Gui et al., 2023). In a recent study by Gui et al. (2023), calponin 2 has been found to increase in AKI resulting from I/R or cisplatin nephrotoxicity. The knockdown of calponin 2 attenuates kidney injury by upregulating hmgcs2, the key enzyme in ketogenesis, and increasing β-hydroxybutyrate levels in mice (Gui et al., 2023). In addition, both ketogenic diet and β-hydroxybutyrate administration have demonstrated efficacy in ameliorating I/R-induced kidney injury (Tajima et al., 2019; Rojas-Morales et al., 2022). Notably, ketone bodies may offer renal protection through mechanisms beyond just energy production. In the study by Tajima et al. (2019), β-hydroxybutyrate can restore the histone acetylation of the FOXO3 promoter, thereby suppressing pyroptosis through the induction of FOXO3 expression. All these findings highlight the needs of further exploration of the metabolic- and non-metabolic-related mechanisms of ketone bodies in AKI.

Metabolic reprogramming, particularly the shift in energy production from the citric acid cycle and oxidative phosphorylation to glycolysis, is a key pathological hallmark of maladaptive kidney repair (Schaub et al., 2021) (Figure 2). The upregulation of glycolysis has long been recognized in the repair and regeneration of proximal tubular cells following ischemic injury. This includes increased production of glycolytic end products and elevated levels of key glycolytic enzymes such as hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2) (Lan et al., 2016). This metabolic shift was further validated by a recent study by Wang et al. (2022), which used high spatial resolution measurements to examine proximal tubular metabolism in situ within the kidney. In the same kidney with ischemic injury, the maladaptive repaired proximal tubules had significantly more lactate accumulation and less citric acid cycle activity compared to those repaired or healthy proximal tubules. Notably, the S3 segment of proximal tubules showed even greater lactate buildup compared to S1/S2 segments. An intriguing observation was that, compared to uninjured proximal tubules in the sham-operated kidneys, the healthy proximal tubules in the repaired kidneys still displayed higher lactate levels and lower concentrations of citric acid cycle metabolites, indicating some degree of prolonged metabolic reprogramming in the kidneys that have undergone repair.

The role of enhanced glycolysis in pathology has been a subject of intense study in recent years, yielding controversial results. In research using zebrafish models to investigate the energy metabolism, CXCL12 and MYC have been pinpointed to promote renal repair through the upregulation of glycolysis (Yakulov et al., 2018). However, the subsequent validation experiments using mouse models with CXCL12 or MYC knockout in renal tubules have failed to distinguish the renal injury and repair phase, leaving the conclusion obscure. In another study utilizing a PFKFB2 mutant knock-in mouse model, glycolysis has been suppressed, yet renal fibrosis has markedly increased, following ureteral obstruction or folic acid-induced injury (Lee et al., 2020). Conversely, data from our research and those of others have indicated that inhibiting glycolysis can significantly enhance renal repair and ameliorate renal fibrosis (Ding et al., 2017; Wei et al., 2019; Shen et al., 2020; Ye et al., 2021; Yang et al., 2023c; Yang et al., 2023d; Xu et al., 2023). Specifically, glycolysis inhibition can reduce macrophage infiltration and differentiation, fibroblast activation and proliferation, and the pericyte–fibroblast transition (Shen et al., 2020; Ye et al., 2021; Yang et al., 2023c; Yang et al., 2023d; Xu et al., 2023). The role of glycolysis in renal tubules is complicated. We have found that glycolysis inhibitors did not suppress the partial epithelial–mesenchymal transition in cultured proximal tubular cells but decreased renal tubular cell apoptosis in the obstructed kidneys (Wei et al., 2019). It is possible that the differentially injured proximal tubular cells may further regulate renal inflammation and fibroblast activation (Shen et al., 2020; Yang et al., 2023d; Kayhan et al., 2023). Overall, glycolysis inhibition may have divergent effects on different renal cells.

The increase in glycolysis levels in repaired kidneys is always associated with the dysregulation of lipid metabolism (Harzandi et al., 2021). This is particularly evident in proximal tubules, which rely heavily on fatty acid β-oxidation for energy production and contain abundant peroxisomes and mitochondria. These cells are especially susceptible to mitochondria damage and lipid metabolism dysregulation after kidney injury, resulting in lipid accumulation in the kidney and the presence of fatty acids in urine (Bataille et al., 2018; Jang et al., 2020a; Dhillon et al., 2021; Gewin, 2021; Gu et al., 2022; Rinaldi et al., 2022). Genome-wide transcript profiling has identified various patterns of aberrant expression of fatty acid metabolism regulators in proximal tubular cells across different types of fibrotic kidneys after ischemia/reperfusion, folic acid injury, or kidney transplant (Bataille et al., 2018; Dhillon et al., 2021; Rinaldi et al., 2022). In the folic acid-treated kidneys, estrogen-related receptor alpha, a nuclear receptor pivotal in regulating fatty acid oxidation, has been reported to promote proximal tubular cell lipid metabolism and differentiation (Dhillon et al., 2021). In I/R-induced kidney injury, αKlotho deficiency-induced lipid droplet accumulation in the kidney is associated with CKD transition (Wang et al., 2023). In addition, protein phosphatase 2Acα, which can inhibit fatty acid β-oxidation and simultaneously enhance glycolysis through the dephosphorylation of phospho-acetyl-CoA, is induced in the fibrotic kidneys (Gu et al., 2022). This enzyme induction suppresses kidney repair by increasing tubular cell death and fibrosis in the obstructed kidney. The enhanced fatty acid β-oxidation by PGC1α activator also inhibits the pericyte–myofibroblast transition to prevent AKI–CKD transition (Xu et al., 2023). However, our current understanding of the roles of these fatty acid metabolism-related genes in kidney repair remains incomplete. Additionally, how peroxisomes participate in this lipid metabolism regulation is unclear.

Amino acids, serving as fundamental components for protein synthesis, play a crucial role in kidney repair. Essential amino acids are transported to the kidney via the bloodstream and are absorbed by kidney cells through amino acid transporters (Broer, 2008). However, studies examining plasma concentrations of amino acids have yielded controversial results (Bednarek-Skublewska et al., 2002; Kumar et al., 2012; Ikeda, 2020; Lanzon et al., 2021; Mahbub et al., 2021). While most studies report a decrease in BCAAs in plasma (Bednarek-Skublewska et al., 2002; Kumar et al., 2012; Ikeda, 2020), Mahbub et al. (2021) have observed increased BCAAs in the blood of CKD patients, correlating strongly with a decline in the estimated glomerular filtration rate. One possible reason is that dialysis patients might experience nutritional loss during the treatment process (Ikeda, 2020). It is noteworthy that change patterns of BCAA and AAA are different (Mahbub et al., 2021). In a recent study by Pillai et al. (2019), the diet supplement effect of BCAA or AAA has been examined in the 5/6 nephrectomy rat model. Intriguingly, BCAA and AAA supplements have shown divergent impacts on kidney injury and fibrosis development. BCAA supplements promote fibrosis, while AAA supplements are protective for the kidneys. Conversely, another animal study has reported conflicting findings regarding the role of AAAs, indicating that a low AAA diet protects rats from adenine-induced nephrotoxicity, reducing proteinuria, fibrosis, and inflammation (Barba et al., 2021). Overall, our understanding of amino acid homeostasis in kidney repair remains quite limited.