Facts

  • Metabolic reprogramming refers to the changes in cellular metabolic pathways that are necessary to support cell growth and proliferation.

  • Metabolic reprogramming is characterized by mitochondrial biosynthesis dysfunction, increased glycolysis, and abnormal lipid and amino acid metabolism.

  • Oxidative stress, inflammatory damage, abnormal autophagy and apoptosis caused by metabolic disorders contribute to the development of DKD and ultimately renal fibrosis.

  • While current conventional treatments for DKD can slow down disease progression to some extent, they come with adverse effects, increased risk of cardiovascular disease, and eventual loss of renal function.

Open questions

  • Renal cells exhibit distinct physiological characteristics and functions. Is the mechanism of metabolic reprogramming consistent across these diverse cell types?

  • DKD is a chronic pathological process, does the metabolic disorders of renal cells change as the disease progresses?

  • Could it be a promising and safe therapeutic approach for managing DKD by regulating metabolic reprogramming and restoring normal mitochondrial function?

Introduction

It is estimated that approximately 40% of diabetics can develop diabetic kidney disease (DKD), which is responsible for end-stage renal disease (ESRD) worldwide [1]. Metabolic disorders, such as hyperglycemia and hyperlipidemia, can damage renal cells through oxidative stress-mediated injury, inflammatory response, apoptosis, and autophagy, leading to renal tubulointerstitial inflammation and fibrosis, glomerular hypertrophy, glomerulosclerosis and ultimately renal insufficiency [2]. Metabolic reprogramming is a mechanism by which cells change metabolic patterns to meet energy needs for cell survival and growth [3]. Recently, it has been found that metabolic reprogramming was triggered by impaired mitochondrial biogenesis in a high-glucose environment and played a crucial role in the pathogenesis of DKD [4,102].

Recent studies have shown that SGLT2 inhibitor drugs play a role in regulating amino acid metabolism in DKD. Kogot et al. discovered in mice that dapagliflozin can reduce renal fibrosis by suppressing the abnormal expression of collagen and amino acid transport proteins via mTORC1 inhibition [103]. Lu et al. conducted a 12-week study administering empagliflozin to db/db mice, resulting in decreased levels of KYN and increased expression of acetyl-CoA and NAD+ in the kidneys. The researchers proposed that empagliflozin may activate the crucial enzyme for NAD+ synthesis, potentially restoring the tryptophan metabolic pathway in DKD [104].

Glucagon-like peptide-1 receptor (GLP-1R) agonist

Glucagon-like peptide-1(GLP-1), an enteroglucagon hormone produced by intestinal L-cells, activates the Glucagon-like peptide-1 receptor (GLP-1R) to enhance insulin secretion and inhibit glucagon secretion in a glucose concentration-dependent manner. Additionally, it can delay gastric emptying and reduce food intake through central appetite suppression, ultimately leading to lower blood glucose levels. Recent studies have also shown the presence of GLP-1R in kidney cells, where chronic high glucose stimulation may lead to GLP-1R ubiquitination and subsequent kidney cell damage [105].

Recent studies have shown that GLP-1 agonists play a role in regulating lipid metabolism. Some meta-analysis by Yao and Sun et al. revealed that GLP-1 agonists have notable lipid-lowering effects compared to glucose-lowering drugs like insulin, including reducing LDL, cholesterol, and triglycerides [106]. It has been proposed that GLP-1 agonists may hinder lipase secretion in the intestinal lumen, thereby slowing gastric emptying and inhibiting fat absorption [107]. Exendin-4, as a GLP-1R agonist, inhibits ERK1/2 by activating the PI3K/AKT signaling pathway. In addition, it increases the phosphorylation of AMPK and ACC and promotes the expression of PPAR-α and CPT1, which not only promotes lipolysis and inhibits adipogenesis, but also exerts an anti-inflammatory effect in glomerular endothelial cells [108]. Further research is needed to fully understand the mechanisms of GLP-1 agonists in lipid absorption and metabolism.

Traditional Chinese medicines

Traditional Chinese medicine (TCM) has a long history in treating DKD, either alone or in combination with conventional drugs like ACEI/ARB’s, showing positive therapeutic effects [109, 110]. Recent studies have demonstrated that biologically active phytochemicals in TCM can modulate metabolic reprogramming in DKD with minimal adverse effects in clinical settings [111]. For example, the Zhenqing recipe, containing Fructus Ligustri Lucidi, Eclipta Prostrata, and Dioscorea opposite, was found to inhibit the expression of SREBP-1C and its target genes, ACC and FAS, in diabetic rats, leading to a significant reduction in triglycerides and cholesterol levels [112]. Morroniside, an iridoid glycoside from Cornus officinalis Sieb, was shown by Gao et al. to up-regulate the expression of PGC-1α, LXR, ABCA1, and ApoE, promoting intracellular cholesterol efflux in the kidneys of diabetic mice [113]. Qin et al. discovered that berberine has the ability to activate the PGC-1α/LXR signaling pathway in db/db mouse foot cells. This activation restores mitochondrial homeostasis, normalizes fatty acid oxidation, reverses metabolic disorders, and repairs cellular damage [114]. The precise targeting mechanism of Chinese herbs for DKD requires further investigation. Current research indicates that various biologically active plant components found in Chinese herbs show promise in treating DKD effectively. However, a deeper understanding of the therapeutic mechanisms of these components is necessary to achieve precise treatment of DKD using Chinese herbs.

Emerging drugs

With the advancing comprehension of mitochondrial metabolic reprogramming, there is a growing number of targeted therapeutic agents being uncovered. Recent studies have shown that artemether treatment in diabetic mice led to decreased levels of branched-chain amino acids and citrulline, indicating a potential alteration in amino acid metabolism in DKD [115]. Additionally, artemether was found to upregulate the expression of PGC-1α and MPC in the renal cortex of diabetic mice, enhancing pyruvate oxidation in the mitochondrial matrix and regulating mitochondrial function to ameliorate renal injury [116]. Clinical trials focusing on targeted drug therapies for metabolic reprogramming have been emerging. For instance, fenofibrate (NCT03869931), a PPARα agonist, has been shown to restore fatty acid oxidation and is commonly used for hypertriglyceridemia treatment. Annelie et al. discovered that inhibition of VEGF-B signaling reduced lipid accumulation in the kidney, mitigated renal lipotoxicity, and prevented renal dysfunction [117]. The effectiveness of 2H10 (NCT04419467), a monoclonal antibody targeting VEGF-B, is currently being investigated in patients with DKD. Furthermore, Dorzagliatin (NCT06222476), a glucokinase activator serving as a novel hypoglycemic agent, aids in enhancing the body’s intrinsic capacity to regulate glucose levels.

The treatment program for DKD is now more advanced, incorporating lifestyle improvements alongside symptomatic medications to regulate blood glucose, blood lipids, and blood pressure. In cases of end-stage DKD, renal replacement therapy is the only option. With the discovery of metabolic reprogramming in DKD and its impact on kidney damage, there is potential for drugs targeting metabolic reprogramming to halt disease progression at a pathogenic level.

Conclusions

DKD is a glomerular disease that results from diabetes mellitus, and is classified as one of its microvascular complications. The increased sugar concentration in the blood causes hyperperfusion and hyperfiltration of the glomeruli, as well as excessive tubular reabsorption, leading to an increase in renal oxygen consumption. This altered hemodynamics in the kidney, along with activation of the local RAS system, can lead to vascular lesions and a reduction in blood vessels. Stimulation by high glucose and hypoxia can cause mitochondrial dysfunction in renal cells. This can lead to abnormal expression of regulatory factors, such as HIF-α and SIRT3, which can affect a range of signaling pathways and stimulate the onset of abnormal glycolysis and amino acid metabolism. Additionally, this can inhibit the FAO response, which can enhance lipotoxicity. The production of large amounts of ROS and inflammatory factors can result in oxidative stress damage, inflammatory damage, autophagy, and apoptosis in renal cells (Table 2). Ultimately, this can lead to renal fibrosis and renal dysfunction (Fig. 2).

Table 2 Summary of cellular injuries in DKD.
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Fig. 2: Overview of the pathogenesis of diabetic kidney disease (DKD).
figure 2

In a healthy kidney, the glomerular filtration barrier is formed by intact glomerular endothelial cells, basement membranes, and podocytes. This barrier effectively prevents the filtration of macromolecules like plasma albumin from the blood. The contractile action of mesangial cells regulate the tubular diameter of the afferent and efferent arterioles, thereby controlling the glomerular filtration rate. Additionally, mesangial cells support the position of vascular collaterals. Tubular epithelial cells play a role in regulating the formation of primary urine through functions like reabsorption, secretion, and excretion. However, hyperglycemia-induced changes in kidney hemodynamics, activation of the RASS, generation of AGEs leading to mitochondrial metabolic reprogramming, and excessive release of ROS trigger a cascade of signaling pathways, cytokines, and transcription factors. These factors contribute to the development of various pathological responses in renal cells, including inflammation, autophagy, apoptosis, and fibrosis.

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DKD is a condition in which high blood glucose levels lead to a series of kidney damages. Lowering blood glucose levels alone cannot prevent the development of DKD. The pathogenesis of DKD is complex, as it involves extensive damage caused by the reprogramming of mitochondrial metabolism in kidney cells. Therefore, treatment for DKD should focus on correcting mitochondrial metabolic reprogramming and restoring normal glucose and fatty acid metabolism, in addition to controlling blood glucose levels. Understanding the role of mitochondrial metabolic reprogramming in various cells during the development of DKD is crucial for comprehending the disease’s pathogenesis and develo** more effective nephroprotective therapies.