2. Sugar Or Fat? Renal Tubular Metabolism Reviewed in Health And Disease

Metabolism of the Injured Kidney

As previously mentioned, the proximal tubule is the mainstay of solute reabsorption and abundant mitochondria are necessary for the production of ATP required to support the transporters needed to recycle the solute load. ATP production by mitochondrial ETCs requires oxygen. Therefore, tubular segments, especially proximal tubules, have high oxygen demand, making these cells susceptible to renal injury. The S3 segment of the proximal tubule is particularly susceptible to injury because it is located deep in the kidney and has low blood flow and oxygen tension. Impaired oxygen delivery due to hemodynamic disruption (e.g., sepsis and extracorporeal circulation) is a key feature of many renal injuries and leads to tubular hypoxia and impaired function. High expression of transporter proteins in the proximal tubule also makes this tubular segment vulnerable to injury from toxins (e.g., mercury, lead, and aristolochic acid) or drugs (e.g., aminoglycosides). Injury can occur as acute kidney injury (AKI) or chronic kidney disease (CKD), where the injury is sustained, such as in hypertension or diabetes. In clinical practice, patients with AKI are at a much greater risk of developing CKD, and patients with CKD are more likely to develop AKI, suggesting that the two processes are interrelated. However, there may be important differences in the nutritional availability of the kidney during recovery from AKI compared to CKD. Therefore, the literature on AKI and CKD metabolism will be reviewed separately.

Renal Tubular Metabolism in AKI

Acutely injured renal tubules may undergo apoptotic or necrotic death or may shed due to reduced adhesions resulting from altered integrin expression. Surrounding epithelial cells de-differentiate, migrate, and proliferate to repair the damaged tubular epithelium. How these surviving epithelial cells respond can determine whether the kidney experiences successful repair or progresses to tubulointerstitial fibrosis.

AKI and Anaerobic Glycolysis

There is strong evidence that FAO, the preferred metabolic pathway for energy production in the proximal tubule, is inhibited in AKI, favoring glucose metabolism to lactate (Figure 3). Glycolysis technically refers to the metabolism of glucose to pyruvate, and the term "anaerobic glycolysis" is used here to denote the metabolism of glucose to pyruvate followed by lactate, in contrast to glucose oxidation (glucose is metabolized to pyruvate and then enters the TCA cycle). Increased glucose uptake and anaerobic glycolysis have also been described in mercuric chloride-induced AKI rats. Ischemia-reperfusion injury (IRI) increases lactate and pyruvate levels in the injured kidney and increases the expression of glycolytic enzymes such as hexokinase 2. These changes appear early in the dedifferentiated tubule, but evidence of hypoxia remains in the late stages of atrophic tubules. Thus, glycolytic metabolism is present in persistently injured dedifferentiated tubules. However, it is unclear whether glycolysis is the mechanism responsible for the failure of tubule recovery or whether it simply reflects persistent injury.

Figure 3. Renal injury alters proximal tubule cell metabolism by suppressing fatty acid oxidation and increasing anaerobic glycolysis. (A) Healthy proximal tubule (PT) cells rely on the utilization of fatty acid oxidation by peroxisomes and mitochondria to generate ATP. Transcription factors such as PCG-1 and PPAR-a increase mitochondrial biogenesis and expression of genes related to fatty acid oxidation. Conversely, glycolysis is not a big source of energy in the uninjured proximal tubule. Kidney injury impairs mitochondrial function and decreases the expression of PGC-a and PPAR-a (B). Therefore fatty acid oxidation declines and injured PT cells rely on glycolysis to help meet energetic demandsAnaerobic glycolysis leads to increased levels of lactic acid. Created by BioRender.com.

AKI and Glucose Oxidation

There is strong evidence that the role of renal tubular glucose oxidation in AkI has not been studied as much as glycolysis in proximal tubules producing renal tubules. Glucose oxidation is promoted by pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl coenzyme a, which enters the TCA cycle to form citrate. pDH can be inhibited by the phosphorylation of pyruvate dehydrogenase kinases (PDKs) at the S232, S293, and S300 sites. Hypoxia blocked PDH by inducing PDKs. 7 days after IRI, there was an increase in inhibitory phosphorylation of PDH Ela subunits in the renal tubules, which persisted until 14 days and was accompanied by tubular atrophy, increased glycolytic enzyme expression, and lactate accumulation. This suggests that elevated pyruvate caused by glucose metabolism in hypoxia-injured tubules produces lactate without entering the TCA cycle. Platinum (a chemotherapeutic agent often restricted due to nephrotoxicity) also increases PDH phosphorylation while decreasing renal function. the PDK inhibitor dichloroacetate (DCA) ameliorates cisplatin-induced renal injury, reduces tubular apoptosis, and prevents inhibitory PDH phosphorylation. Thus, efforts to increase pyruvate entry into the TCA cycle or glucose oxidation may be protective for the kidney.

However, DCA also increased peroxisome proliferator-activated receptor-α (PPAR-α), a regulator of FAO, so the beneficial effects may also be due to these metabolic changes.

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AKI, Mitochondrial Injury, and Fatty Acid Oxidation

Mitochondrial damage is an important feature of AKI and is closely related to metabolism. The final step in the production of energy from fatty acids involves the mitochondrial ETC and the regeneration of NAD+ from its reduced form, NADH. Thus, impaired ETC function in damaged mitochondria reduces NAD+, which is required for glycolysis and sustained ATP production from fatty acid or glucose oxidation. animal models of AKI show structural and functional damage to mitochondria, as evidenced by swelling and fragmentation, as well as loss of ETC protein and reduced ATP production. Multiple factors contribute to AKI-induced mitochondrial dysfunction. Hypoxia, a common feature of AKI, leads to an increased accumulation of reactive oxygen species (ROS), which can inhibit ETC enzymes. In AKI, the balance between mitochondrial fusion and fission is disrupted, leading to mitochondrial fragmentation, which sensitizes cells to apoptosis. In addition, sepsis models of AKI show reduced expression of PPARγ coactivator-1α (PGC-1α), an inducer of mitochondrial biogenesis.PGC-1α inhibition is associated with a similar degree of reduced renal function and increased mitochondrial damage. Genetic deletion of PGC-1α in renal tubules exacerbated endotoxin-induced AKI, whereas PGC-1α overexpression was protective against ischemic kidney injury. In conclusion, the hypoxic environment of AKI and the cellular response to these injuries lead to impaired mitochondrial function. Furthermore, restoration of mitochondrial biogenesis by PGC-1α may improve the response to AKI.

Mitochondria are required for the generation of ATP via fatty acid metabolism, thus AKI-induced mitochondrial dysfunction contributes to impaired FAO. pGC-1α activity may enhance cellular respiration, as proximal tubules overexpressing PGC-1α in vitro experiments attenuated TNF-α-induced basal respiratory inhibition. As mentioned above, NAD+ levels, which are essential for FAO, are reduced in AKI. Increased NAD+ depletion via tubular PARPs contributes to lower NAD+:NADH during an ischemic injury in rodents. in addition, metabolomic studies from the urine of iris-injured mice showed impaired expression and NAD+ levels of enzymes involved in NAD+ biosynthesis. However, overexpression of PGC-1α induced NAD+ biosynthesis and rescued NAD+ levels, suggesting that impaired PGC-1α in AKI may promote further injury by decreasing NAD+ levels. In addition, impaired fatty acid metabolism after IRI was attributed to reduced activity of CPT1, the rate-limiting enzyme of FAO. Enhancement of CPT1 with the synthetic compound C75, a fatty acid synthase inhibitor, ameliorates renal injury in rodents. Data with inhibitors need to be confirmed using genetic methods, but these data suggest that impaired FAO may cause, and not just reflect renal injury.

Recent studies suggest that the peroxisome may also play a role in the renal response to AKI, particularly ischemic AKI. The peroxisome preferentially oxidizes VLCFA, a process that generates hydrogen peroxide (H2O2) and requires large amounts of catalase for H2O2 metabolism. Thus, peroxisomes may be important in supporting mitochondrial FAO and scavenging reactive oxygen species (ROS), both of which are dysregulated in AKI. Peroxisomal FAO was measured by VLCFA lignocaine oxidation, and its reduction was proportional to the duration of ischemia. In ischemic and cisplatin-induced AKI, deletion of the deacetylase sirtuin 5 localized to the peroxisome was protective, reducing mitochondria but increasing peroxisomal FAO. In a model of cisplatin injury, treatment with the PPAR-α ligand betaine attenuated renal injury and increased peroxisomal protein expression. Although these data support a protective role for peroxisomes in AKI, further studies that more directly affect peroxisome function are needed to better determine whether increasing peroxisome FAO is protective against AKI.

Taken together, these data suggest that acute injury to the kidney inhibits fatty acid and glucose oxidation, decreases mitochondrial function, and increases glycolysis leading to lactate (Figure 3). Efforts to increase mitochondrial biogenesis and function or to promote fatty acid and glucose oxidation in the renal tubules may improve tubular injury and renal function.

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Renal Tubular Metabolism in CKD

CKD and Fatty Acid Oxidation

Renal metabolism is significantly dysregulated in patients with CKD. Unbiased transcriptomics of microdissected tubular interstitial samples from patients with diabetic and hypertensive CKD showed reduced expression of genes associated with fatty acid, glucose, and amino acid metabolism. Although all metabolic pathways were affected, the expression of enzymes related to fatty acid metabolism was particularly downregulated. More specifically, gene expression of the key FAO regulators Cpt1a and Ppara was reduced in both human and mouse CKD models. In another study, CPT1A levels in human tubules decreased with a decrease in glomerular filtration rate (eGFR) (an indicator of renal function) and an increase in fibrosis rate. Another group of CKD patients had increased accumulation of short- and medium-chain acylcarnitines and decreased eGFR, but no change in long-chain acylcarnitines transported by CPT1a. Blockade of FAO in renal tubules in vitro using etomoxir or ranolazine resulted in higher levels of cell death and dedifferentiation. Dedifferentiated renal tubular cells contribute to the progression of tubulointerstitial fibrosis. the mechanism by which reduced FAO leads to tubular dedifferentiation is not fully understood, but the knockdown of Cpt1a in cultured endothelial cells leads to dedifferentiation via a Smad7/TGF-β-dependent pathway.

AKI causes mitochondrial damage and reduces FAO, and efforts to reduce mitochondrial damage or optimize fatty acid metabolism have improved the response to AKI, as previously described. There is increasing evidence that enhanced mitochondrial biogenesis and/or FAO may also be beneficial in the context of CKD. ppargc1a is a strong inducer of Cpt1a and its gene overexpression in renal tubules reduces folate-induced tubular apoptosis. Pharmacological intervention with fenofibrate and etomoxir to activate PPARα or block CPT1, respectively, was performed in a unilateral ureteral obstruction (UUO) model in which ureteral ligation resulted in the rapid development of renal fibrosis due to counterpressure and inflammation within 5-7 days. Although off-target effects of etomoxir have been reported recently, these data suggest that enhancement of FAO in the renal tubules by Cpt1a or Ppara may improve the response to renal injury.

Recently, gene overexpression of Cpt1a in renal tubules prevented three mouse models of CKD: folic acid nephropathy, UUO, and adenine-induced nephrotoxicity. Folic acid nephropathy consists of a single injection of folic acid leading to tubular crystallization, resulting in tubular interstitial fibrosis. Adenine, administered via diet for several weeks, also induced tubular crystal deposition and fibrosis. cpt1a overexpression improved mitochondrial morphology and ATP production after folate nephropathy in addition to rescuing FAO in isolated tissues as measured by [14C]palmitate studies. These elegant studies strongly suggest that inhibited FAO plays a pathogenic role in the progression of tubulointerstitial fibrosis.

CKD Models and Fatty Acid Oxidation

No rodent CKD model can perfectly reproduce human CKD. many commonly used CKD models have an initial AKI component (e.g. IRI, folate nephropathy, and aristolochic acid nephropathy), and the effect of FAO on AKI may determine the progression of CKD. Many studies related to FAO and CKD have used folic acid models, which raises the question: to what extent the protective effect of FAO is due to its role in the acute phase of injury? One study did show that the protective effect of Cpt1a overexpression persisted even after injury-induced recombination, suggesting that FAO may act after acute injury. However, one day after folic acid injection, doxycycline was given to inducible Cpt1a overexpressing mice, raising the question of whether Cpt1a regulates the acute phase of injury. the UUO model is a classic model of tubulointerstitial fibrosis that is better suited to induce rapidly progressive fibrosis than to assess epithelial injury and repair. Published studies encouragingly suggest that increased FAO may be protective against CKD, but future studies should also investigate the role of FAO in more progressive models reflecting hypertensive nephrosclerosis and/or diabetic nephropathy, two major causes of end-stage renal disease.

Cistanche Tubulosa

Fatty Acid Oxidation and Tubulointerstitial Fibrosis

Several mechanisms suggest that increasing FAO may reduce tubulointerstitial fibrosis. Lipid accumulation in the kidney, either through decreased metabolism, increased uptake, or increased synthesis, is a feature of human CKD. In addition to the downregulation of lipid metabolism, expression of the fatty acid receptor CD36 is upregulated in CKD. The CD36 gene or pharmacological inhibition in mice is protective against hypertensive CKD models. Several research groups have proposed that excess lipids in the kidney promote CKD progression through enhanced inflammation, oxidative stress, and endoplasmic reticulum (ER) stress. Consistent with this, mice deficient in CD36 on a high-fat diet were also protected from UUO-induced kidney injury with suppressed pathways mediating inflammation (e.g. NF-κB) and oxidative stress. Mice lacking proximal tubular carnitine acetyltransferase, an enzyme that exports excess acyl coenzyme products from the mitochondria, spontaneously developed apoptosis, fibrosis, and increased oxidative stress. These findings were accelerated by a high-fat diet and were associated with impaired mitochondrial function. However, CD36 overexpression, while increasing renal tubular fatty acid accumulation, had no significant effect on streptozotocin-induced injury, type I diabetes model, or folic acid nephropathy-induced fibrosis. There is strong evidence to support a role for CD36 and lipotoxicity in CKD progression, but the exact contribution may depend on the injury model and other modifying factors (e.g., diet).

Another putative mechanism by which CPT1a and FAO may reduce fibrosis is through the TGF-β signaling pathway. As mentioned above, endothelial cells lacking Cpt1a have increased dedifferentiation via the TGF-β/Smad7 pathway. Similarly, primary renal tubular cells from Cpt1a overexpressing mice showed attenuated dedifferentiation in response to TGF-β1. These in vitro data need to be validated in vivo, and the question of whether these effects of CPT1a are dependent on FAO remains.

Reduced FAO may also promote tubular atrophy through impaired ATP production, a component of tubular interstitial fibrosis. Etomoxir-dependent inhibition of FAO in tubule cells in vitro inhibits ATP production and increases apoptosis. This suggests that reduced FAO may lead to cell death through impaired ATP production. In renal tubules, increasing Cpt1a improved mitochondrial morphology via EM, suggesting that increasing FAO may also exert a protective effect by improving mitochondrial function. Thus, FAO may reduce tubular injury and tubulointerstitial progression by reducing lipotoxicity-induced oxidative stress and inflammation, decreasing tubular TGF-β signaling, and improving tubular survival through improved ATP production and mitochondrial function. However, the link between FAO and tubulointerstitial fibrosis in CKD requires further studies to confirm these potential mechanisms.

CKD and Anaerobic Glycolysis

Enzymes associated with anaerobic glycolysis are increased in both human and animal models of CKD. This is not surprising since mitochondrial damage is an integral part of CKD and glycolysis leading to lactate production can produce ATP without the need for functioning mitochondria. The role of glycolysis in CKD progression is unclear. In the UUO model, inhibition of glycolysis by 2-deoxyglucose, and injection of lentiviral PKM2 RNAi or zymosan treatment reduces fibrosis as well as myofibroblast activation. The mechanism is thought to be mediated by renal fibroblasts (NRK-49F), with increased lactate content in renal fibroblasts and myofibroblast activation (increased fibronectin expression, α-SMA, and proliferation marker PCNA) after PKM2 treatment. Another group also used purpure in UUO-injured mice and reported reduced fibrosis and tubular apoptosis, although the in vitro effect on stromal production was seen only in fibroblasts and not epithelial cells. These studies suggest that blocking glycolysis prevents fibrosis in the UUO model, although the beneficial effects appear to be mediated primarily through fibroblasts rather than tubule cells.

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Other studies suggest that anaerobic glycolysis may be harmless in CKD. In contrast to the protective effect of blocking PKM on AKI, the PKM activator TEPP-46 reduced the expression of fibronectin and other matrix-related genes in tubules of streptozotocin-treated mice. TEPP-46 also improved podocyte injury and basement membrane thickness, so tubular protection may be due to reduced glomerular injury and proteinuria, rather than directly affecting tubular glycolysis. Another study used a novel genetic approach to explore the role of glycolysis in renal injury. Transgenic mice containing point mutations in the key glycolytic enzyme 6-phosphoglucose-2 kinase/fructose-2,6-bisphosphatase (PFKFB2) inactivation had reduced glycolytic capacity. These transgenic mice with reduced glycolysis were not protected against UUO or folate-induced fibrosis, which was exacerbated in transgenic mice with UUO injury. the UUO model targets distal tubules, and although not exclusively, distal tubules are more inclined to rely on glycolysis for metabolism, so more proximal tubule-specific injury may produce a different outcome. Another possibility is that certain glycolytic capacities may be important for the injury response. If the injury is severe enough, glycolysis may be required to temporarily generate energy until repair occurs. Future studies should explore whether blocking glycolytic capacity after initial renal injury may reduce the progression of tubulointerstitial fibrosis.

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