Abstract

Metabolic reprogramming initially refers to the ability of cancer cell metabolism to adapt to changing environmental conditions in order to meet energy expenditure and proliferation requirements. Recent studies have shown that renal cells also have the ability to metabolically reprogram themselves after kidney injury, and that renal cells in different kidney diseases are metabolically reprogrammed in different ways. Metabolic reprogramming also plays a role in the progression and prognosis of renal disease. Thus, metabolic reprogramming is not only a distinctive feature of renal disease but also an important factor in the pathophysiology of renal disease. Here, we briefly review renal disease and metabolic reprogramming and discuss novel approaches to the treatment of renal disease.

Keywords

Acute Kidney Injury; Chronic Kidney Disease; Diabetic Kidney Disease; Cistanche benefits

Introduction

The idea of metabolic reprogramming originally came from the Warburg effect in cancer cells. Despite the presence of sufficient oxygen, oxidative phosphorylation (OXPHOS) in the mitochondria is inhibited and cells tend to use glycolysis to generate energy. The altered metabolism was first recognized by Nobel laureate Otto Warburg, hence the term Warburg effect or aerobic glycolysis [1]. Although aerobic glycolysis is less efficient than OXPHOS, it provides sufficient energy for survival and the production of structural components [2]. The mechanism and significance of the Warburg effect have been at the center of cancer metabolism research for many years.

However, metabolic reprogramming includes not only the Warburg effect but also other metabolic transformations to adapt to the changing environment. Metabolic reprogramming is not only associated with cancer. Emerging evidence suggests that it is also associated with kidney disease. In this review, we present the latest research in this field that may offer new opportunities for the treatment of kidney disease.

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Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the major genetic disorder associated with end-stage renal disease and is caused by loss-of-function mutations in PKD1 or PKD2. The main feature of ADPKD is the overproliferation of epithelial cells leading to the relentless expansion of cysts. Rowe et al. found that mouse embryonic fibroblasts (MEF) isolated from Pkd1-/- embryos acidified the culture medium faster than Pkd1+/+ cells, suggesting that the Pkd1 mutation causes glucose metabolism defects. In addition, enzymes involved in gluconeogenesis are reduced and those involved in glycolysis are increased, as found in PKD mouse models and human ADPKD kidneys. The study showed that PKD1-/- cells in ADPKD provide energy and promote proliferation primarily through aerobic glycolysis, the first time metabolic reprogramming has been observed in kidney disease. (e researchers also found that 2-deoxyglucose (2DG), a non-metabolizable glucose analog, inhibits glycolysis and suppresses the proliferation of Pkd1-/- cells, thereby reducing the cystic index [3].

Defective glucose metabolism is a prominent feature of ADPKD, and other metabolic pathways are also altered during ADPKD. using untargeted global metabolism, Podrini et al. found that deletion of Pkd1 in the mouse kidney resulted in extensive and coordinated metabolic reprogramming: increased glycolysis, pentose phosphate pathway (PPP), fatty acid synthesis (FAS), and glutamine uptake, and increased tricarboxylic acid (TCA) cycle and fatty acid oxidation (FAO) are reduced [4]. Treatment of Pdk1 mutant mice with glutamine inhibitors before birth slows the progression of ADPKD [5,6]. pkd1-/- cells better utilize glutamine to maintain TCA and fatty acid biosynthesis. These cells utilize glutamine via asparagine synthetase (ASNS), so inhibition of ANSN reduces proliferation and increases apoptosis. The Researchers found that targeting asparagine synthetase (ASNS) to interfere with glutaminolysis and glycolysis slowed the growth and survival of PKD1-/- cells. (These findings suggest that the aerobic glycolytic pathway and PPP can increase the growth of cystic epithelial cells and exacerbate disease progression.

In addition, reduced FAO also exacerbates ADPKD.(e transcription factor MYC reprograms cellular metabolism to maintain rapid proliferation of ADPKD cells, similar to cancer cells. In a mouse model of ADPKD, c-MYC upregulates miR-17 in the cystic kidneys. miR-17 inhibits FAO by directly inhibiting PPARα reprogramming mitochondrial metabolism. e transcription factor PPARα is involved in the regulation of lipid metabolism. Inhibition of miR-17 restores PPARα improves FAO, and improves ADPKD [7,8]. In addition, the PPARα agonist fenofibrate increased PPARα expression and FAO, resulting in a 60% reduction in vesicle volume [9]. Thus, combinations targeting metabolic modulators may be a promising therapeutic approach for ADPKD.

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Acute Kidney Injury

Acute kidney injury (AKI) can be caused by a variety of factors, including ischemic or hypoxic injury, infection, and toxins [10]. The corresponding animal models are the AKI model, renal ischemia-reperfusion injury model, LPS-induced AKI model, and nephrotoxicity model (cisplatin and radiocontrast). The key causative factor of AKI is tubular epithelial cell (TEC) injury. TECs have high energy expenditure levels and high baseline metabolic rates to continuously reabsorb urobilinogen components, such as water, amino acids, and glucose. Fatty acid metabolism is the main metabolic pathway in TECs, as this pathway is the most efficient in generating energy. However, in AKI [11], TECs are reprogrammed to use aerobic glycolysis. One of the main causes of this phenomenon is mitochondrial damage; since mitochondria are the site of fatty acid metabolism, proximal tubule cells are shifted to the glycolytic pathway to compensate for the energy deficit. This metabolic shift is necessary for the development of training immunity [12] early in lp-induced AKI, and it is an effective early response to injury. However, a persistent pro-inflammatory state can worsen renal function and prognosis. It is important to switch glycolysis back to OXPHOS to shut down inflammation. Several studies have also shown that inhibiting aerobic glycolysis and increasing OXPHOS protects the organ and improves survival [13,14]. The specific molecular mechanisms were further explored by Zhou et al. The researchers showed that endothelial-type nitric oxide synthase (eNOS) can convert pyruvate kinase M2 (PKM2) to s -nitrosylated PKM2 (SNO-PKM2) via SNO-CoA. (The conversion renders PKM2 unable to catalyze phosphoenolpyruvate, decreases glycolysis, and increases the pentose phosphate pathway (PPP) and serine synthesis. Ultimately, this metabolic reprogramming increases lipid, protein, and nucleotide synthesis, thereby promoting TEC repair and alleviating AKI. (The findings suggest that eNOS can convert glucose utilization from energy production to tissue regeneration after AKI [15].

Another study showed that human umbilical cord mesenchymal stromal cells (UC-MSCs) promoted renal tubular repair in cisplatin-induced AKI. Cisplatin decreased the expression of TEC genes involved in mitochondrial energy production, including amino acid metabolism, urea cycle, fatty acid metabolism, and electron transport chain components.UC-MSCs were able to repair and replenish mitochondria and increase gene expression of electron transport chain components and proteins involved in ATP production, allowing damaged TECs to reprogram their metabolism to maintain energy supply [16]. We suggest that UC-MSCs can protect TECs and promote regeneration after AKI.

If cells fail to switch from aerobic glycolysis to OXPHOS [17] and FAO [18], renal fibrosis and further CKD may result [19].

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Chronic Kidney Disease

Tubulointerstitial fibrosis is common in all end-stage chronic kidney diseases (CKDs) caused by various pathological alterations. The major activators of fibrosis include the activation of renal endowment fibroblasts and transdifferentiation of TECs [20,21]. Increased glycolysis of renal endowment fibroblasts and defective lipid metabolism of TECs are the main types of metabolic reprogramming in the progression of CKD. An important feature of renal tubular interstitial fibrosis is the sustained activation of intrarenal fibroblasts. The superior fibroblast factor TGFβ1 induces a shift from OXPHOS to aerobic glycolysis in renal myofibroblasts and enhances glutamine metabolism. Thus, the metabolic shift to aerobic glycolysis decreased the expression of acetyl coenzyme a, which upregulated the expression of histone 3-related genes [22] and increased the expression of fibrogenic genes [23]. In addition, enhanced glutamine metabolism is required to support the biosynthetic requirements of renal myofibroblasts [24]. Metabolic reprogramming is highly correlated with the development of renal interstitial fibrosis [25].

In a study of TECs, Kang et al. found that TGF-β1 disrupts renal tubular fatty acid metabolism via SMAD3 and PGC-1α in a mouse model of folate nephropathy (FAN) and is involved in tubulointerstitial fibrosis. Restoration of FAO by genetic or pharmacological intervention protected mice from tubulointerstitial fibrosis [18]. (e team also found that direct binding of Jag1/ Notch2 to mitochondrial transcription factor A (Tfam) played a key role in reducing FAO and TEC transdifferentiation. overexpression of Tfam in TECs prevented notch-induced metabolic reprogramming and the development of renal fibrosis. Our study also showed that TEC oxygen consumption and dysfunctional lipid and glucose metabolism were significantly reduced in the FAN mouse model. We also found that exercise counteracts metabolic reprogramming and fibrogenesis via myostatin iris [27].

Accordingly, the feasibility and efficacy of targeting renal lipid metabolic pathways (including CD36, CPT1/2, PPARs, peroxisome proliferator-activated receptor-c coactivator (PGC-1α), proprotein convertase subtilisin/Kexin type 9 (PCSK9) and non-coding RNA) to ameliorate fibrosis have been explored in many preclinical trials. Although clinical trials targeting these emerging modulators are currently lacking, they represent promising strategies for preventing CKD progression.

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Diabetic Kidney Disease

Diabetic nephropathy (DKD) is one of the major microvascular complications of diabetes and has become a major cause of end-stage renal disease. Diabetes affects every type of cell in the kidney, including podocytes, TECs, glomerular endothelial cells, and thylakoid cells. Among them, podocytes and TECs play a key role in the pathogenesis of DKD [29,30]. Diabetes mellitus elevates blood glucose and lipids, leading to metabolic disorders and dysfunction [31,32]. In the renal cortex of DKD, glycolysis, and fatty acid metabolism are increased to compensate for the loss of ATP in the TCA cycle. Glutamate and aspartate metabolism are increased and PPP is decreased [33]. It has been shown that metabolic changes regulated by the lncRNA-mRNA co-expression network are associated with metabolic reprogramming in DKD [34,35].

Regarding the podocyte, a study published in Nature Medicine performed a proteomic analysis of glomeruli from patients with extreme diabetes duration (≥50 years) with and without DKD and showed that 7 of the 12 top-ranked pathways were associated with glucose metabolism and glycolysis. (e Researchers found that enzymes associated with glucose metabolism in podocytes promoted the metabolism of excess free glucose in cells and reduced the accumulation of toxic glucose products in cells, thus protecting podocytes from hyperglycemic toxicity. In addition, hyperglycemia and diabetes reduce the formation of PKM2 tetramers, thereby impairing glycolysis. Foot cell-specific PKM2 knockout diabetic mice exhibited worse proteinuria and glomerular pathology than wild-type mice, and pharmacological activation of PKM2 reversed the elevation of toxic glucose metabolites and mitochondrial dysfunction induced by high glucose, which was protective against DKD [36].

Metabolic reprogramming in TECs also plays an important role in the pathogenesis of DKD. Diabetic renal fibrosis is associated with aberrant glycolysis in TECs. excessive glycolysis in DKD is induced by SIRT3 deficiency through the TGFβ-smad3 signaling pathway. sIRT3 deficiency converts PKM2 tetramers to PKM2 dimers, which can be translocated to the nucleus, promoting transcription of pro-glycolytic enzymes and increasing the production of HIF1α and IL1β. Inhibition of aberrant glycolysis disrupts metabolic reprogramming and inhibits fibrosis in DKD [37]. Although this finding may seem contradictory, the former study focused on the tetrameric active form of PKM2, whereas the latter studied the glycolytically inactivated dimeric form of PKM2, which can translocate to the nucleus to regulate gene expression and induce aberrant glycolysis. Furthermore, TECs are highly proliferative and utilize mainly fatty acids, whereas podocytes are almost quiescent [38] and utilize anaerobic glycolysis [39]. This may explain the differences in metabolic reprogramming of different cells under the same disease, depending on the underlying metabolic type of these cells. The findings suggest that metabolic reprogramming in renal diseases is complex and diverse. Therefore, highly specific targeting in specific renal cells will be difficult but will be key for future therapies.

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Other Kidney Diseases

Different types of glomerulonephritis may have the same metabolic reprogramming. It has been shown that in nephrotic syndrome (NS) and ANCA-associated vasculitis (AAV), TCA cycle, FAO, and glutaminolysis-related gene expression was suppressed in the glomerular compartment compared with normal controls, whereas PPP gene expression was significantly elevated in NS and AAV compared with normal controls. Elevated PPP factor expression was also observed in the glomerular interstitial compartment and tubulointerstitial compartment, and a significant negative correlation between PPP factor expression and GFP was observed in both glomerular and tubulointerstitial compartments.PPP factor expression in the tubulointerstitial compartment was also associated with an increased degree of fibrosis. Studies also suggest that renal monocytes/macrophages may be the main contributors to PPP factor expression in these renal diseases [40].

PPP not only generates NADPH and maintains redox homeostasis, which may be particularly important for cells in a state of oxidative stress, but also synthesizes various cellular components. Activation of PPP promotes T cell proliferation and induces cytokine production by T cells [41] and macrophages [42]. there is a strong correlation between PPP and lymphocyte activation in SLE [43] and TNF activation in AAV [40]. (Thus, the reprogramming of inflammatory cell metabolic pathways may be the same in different types of glomerulonephritis, especially in patients with inflammatory nephritis [44].

Conclusion

According to these studies, metabolic reprogramming plays an important role in kidney disease. However, many of the cited studies examined only mRNA levels or metabolite concentrations, which are not necessarily the same as changes in carbon flux. Therefore, future work should focus on this limitation to validate the role of metabolic reprogramming.

Metabolic reprogramming is not only a consequence of kidney disease progression but also affects the outcome and prognosis of kidney disease. The kidney is composed of multiple cell types, and different cell types exhibit different baseline metabolism and metabolic reprogramming in different renal diseases. For us, metabolic reprogramming is not a simple alteration of energy or glucose metabolism, but an adaptive mechanism specific to kidney cell type and disease. However, the full characterization of the metabolism of all renal cell types has not been determined. Future studies should focus on the adaptation of specific metabolic pathways in renal diseases. In addition, the downstream roles of key molecules in metabolic reprogramming are unclear, and their functions and mechanisms need to be further explored to provide new targets for early diagnosis and treatment of renal diseases. Understanding these mechanisms will help to identify new therapeutic targets and create new opportunities for the treatment of renal diseases.

REFERENCES

[1] W. Otto, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956.

[2] M. G. Vander Heiden, L. C. Cantley, and C. B. Thompson, “Understanding the Warburg effect: the metabolic requirements of cell proliferation,” Science, vol. 324, no. 5930, pp. 1029–1033, 2009.

[3] I. Rowe, M. Chiaravalli, V. Mannella, et al., “Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy,” Nature Medicine, vol. 19, no. 4, pp. 488–493, 2013.

[4] C. Podrini, I. Rowe, R. Pagliarini, et al., “Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways,” Communications biology, vol. 1, Article ID 194, 2018.

[5] C. Marco, R. Isaline, M. Valeria, et al., “2-Deoxy-d-Glucose ameliorates PKD progression,” Journal of the American Society of Nephrology: Journal of the American Society of Nephrology, vol. 27, no. 7, pp. 1958–1969, 2016.

[6] E. M. Flowers, J. Sudderth, L. Zacharias, et al., “Lkb1 deficiency confers glutamine dependency in polycystic kidney disease,” Nature Communications, vol. 9, no. 1, Article ID 814, 2018.

[7] N. Bougarne, B. Weyers, S. J. Desmet, et al., “Molecular actions of PPARα in lipid metabolism and inflammation,” Endocrine Reviews, vol. 39, no. 5, pp. 760–802, 2018.

[8] S. Hajarnis, R. Lakhia, M. Yheskel, et al., “microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism,” Nature Communications, vol. 8, no. 1, Article ID 14395, 2017.

[9] R. Lakhia, M. Yheskel, A. Flaten, E. B. Quittner-Strom, W. L. Holland, and V. Patel, “PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice,” American Journal of Physiology-Renal Physiology, vol. 314, no. 1, pp. F122–F131, 2018.

[10] A. Zuk and J. V. Bonventre, “Acute kidney injury,” Annual Review of Medicine, vol. 67, no. 1, pp. 293–307, 2016.

[11] J. A. Smith, L. J. Stallons, and R. G. Schnellmann, “Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury,” American Journal of Physiology Renal Physiology, vol. 307, no. 4, pp. F435–F444, 2014.

[12] S. C. Cheng, J. Quintin, R. A. Cramer, et al., “mTOR- and HIF- 1α-mediated aerobic glycolysis as the metabolic basis for trained immunity,” Science, vol. 345, no. 6204, Article ID 1250684, 2014.

[13] T. T. Mei, Z. K. Zsengeller, A. H. Berg, et al., “PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection,” Nature, vol. 531, no. 7595, pp. 528–532, 2016.

[14] S. Peerapornratana, C. L. Manrique-Caballero, H. G´omez, and J. A. Kellum, “Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention, and treatment,” Kidney International, vol. 96, no. 5, pp. 1083–1099, 2019.

[15] H.-L. Zhou, R. Zhang, P. Anand, et al., “Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury,” Nature, vol. 565, no. 7737, pp. 96–100, 2018.

[16] L. Perico, M. Morigi, C. Rota, et al., “Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function,” Nature Communications, vol. 8, no. 1, Article ID 983, 2017.

[17] S. H. Han, L. Malaga-Dieguez, F. Ching, et al., “Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism,” Journal of the American Society of Nephrology, vol. 27, no. 2, pp. 439–453, 2016.

[18] H. M. Kang, S. H. Ahn, P. Choi, et al., “Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development,” Nature Medicine, vol. 21, no. 1, pp. 37–46, 2015.

[19] H. Gomez, J. A. Kellum, and C. Ronco, “Metabolic reprogramming and tolerance during sepsis-induced AKI,” Nature Reviews Nephrology, vol. 13, no. 3, pp. 143–151, 2017.

[20] V. S. Lebleu, G. Taduri, J. O’Connell, et al., “Origin and function of myofibroblasts in kidney fibrosis,” Nature Medicine, vol. 19, no. 8, pp. 1047–1053, 2013.

[21] W. Kriz, B. Kaissling, and M. Le Hir, “Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy?” Journal of Clinical Investigation, vol. 121, no. 2, pp. 468–474, 2011.

[22] E. R. Smith, B. Wigg, S. Holt, and T. Hewitson, “TGF-β1 modifies histone acetylation and acetyl-coenzyme A metabolism in renal myofibroblasts,” American Journal of Physiology Renal Physiology, vol. 2019, 2019.

[23] T. Irifuku, S. Doi, K. Sasaki, et al., “Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression,” Kidney International, vol. 89, no. 1, pp. 147–157, 2016.

[24] T. D. Hewitson and E. R. Smith, “A metabolic reprogramming of glycolysis and glutamine metabolism is a requisite for renal fibrogenesis-why and how?” Frontiers in Physiology, vol. 12, Article ID 645857, 2021.

[25] X. N. Yin, J. Wang, L. F. Cui, and W. X. Fan, “Enhanced glycolysis in the process of renal fibrosis aggravated the development of chronic kidney disease,” European Review for Medical and Pharmacological Sciences, vol. 22, no. 13, pp. 4243–4251, 2018.

[26] S. Huang, J. Park, C. Qiu et al., “Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming,” PLoS Biology, vol. 16, no. 9, Article ID e2005233, 2018.

[27] H. Peng, Q. Wang, T. Lou, et al., “Myokine mediated musclekidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys,” Nature Communications, vol. 8, no. 1, Article ID 1493, 2017.

[28] Y. Chen, X. Chen, and S. Zhang, “Druggability of lipid metabolism modulation against renal fibrosis,” Acta Pharmacologica Sinica, pp. 1–15, 2021.

[29] K. Reidy, H. M. Kang, T. Hostetter, and K. Susztak, “Molecular mechanisms of diabetic kidney disease,” Journal of Clinical Investigation, vol. 124, no. 6, pp. 2333–2340, 2014.

[30] C. W. Sydney and N. L. Kar, “(e pathogenic role of the renal proximal tubular cell in diabetic nephropathy,” Nephrology Dialysis Transplantation, vol. 27, no. 8, pp. 3049–3056, 2012.

[31] M. Stumvoll, B. J. Goldstein, and T. W. van Haeften, “Type 2 diabetes: principles of pathogenesis and therapy,” e Lancet, vol. 365, no. 9467, pp. 1333–1346, 2005.

[32] F. Bonacina, A. Baragetti, A. L. Catapano, and G. D. Norata, “the interconnection between immuno-metabolism, diabetes, and CKD,” Current Diabetes Reports, vol. 19, no. 5, Article ID 21, 2019.

[33] K. M. Sas, P. Kayampilly, J. Byun, et al., “Tissue-specific metabolic reprogramming drives nutrient efflux in diabetic complications,” JCI Insight, vol. 1, no. 15, Article ID e86976, 2016.

[34] L. Wen, Z. Zhang, R. Peng, et al., “Whole transcriptome analysis of diabetic nephropathy in the DB/DB mouse model of type 2 diabetes,” Journal of Cellular Biochemistry, vol. 120, no. 10, pp. 17520–17533, 2019.

[35] L. M. Hinder, M. Park, A. E. Rumora et al., “Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease,” Journal of Cellular and Molecular Medicine, vol. 21, no. 9, pp. 2140–2152, 2017.

[36] W. Qi, H. A. Keenan, Q. Li et al., “Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction,” Nature Medicine, vol. 23, no. 6, pp. 753–762, 2017.

[37] S. P. Srivastava, J. Li, M. Kitada, et al., “SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis,” Cell Death & Disease, vol. 9, no. 10, Article ID 997, 2018.

[38] T. Imasawa and R. Rossignol, “Podocyte energy metabolism and glomerular diseases,” the International Journal of Biochemistry & Cell Biology, vol. 45, no. 9, pp. 2109–2118, 2013.

[39] P. T. Brinkkoetter, T. Bork, S. Salou, et al., “Anaerobic glycolysis maintains the glomerular filtration barrier independent of mitochondrial metabolism and dynamics,” Cell Reports, vol. 27, no. 5, pp. 1551–1566, 2019.

[40] P. C. Grayson, S. Eddy, J. N. Taroni et al., “Metabolic pathways and Immunometabolism in rare kidney diseases,” Annals of the Rheumatic Diseases, vol. 77, no. 8, 2018.

[41] Y. Zhen, H. Fujii, S. V. Mohan, J. J. Goronzy, and C. M. Weyand, “Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells,” Journal of Experimental Medicine, vol. 210, no. 10, pp. 2119–2134, 2013.

[42] A. Haschemi, P. Kosma, L. Gille, et al., “(e sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism,” Cell Metabolism, vol. 15, no. 6, pp. 813–826, 2012.

[43] L. Morel, “Immunometabolism in systemic lupus erythematosus,” Nature Reviews Rheumatology, vol. 13, no. 5, pp. 280–290, 2017.

[44] S. Zhang, H. Xin, L. Yan, et al., “Skimmin, a coumarin from hydrangea panicula ta, slows down the progression of membranous glomerulonephritis by anti-inflammatory effects and inhibiting immune complex deposition,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, no. 1–3, Article ID 819296, 10 pages, 2013.