Acute Kidney Injury And Lipid Metabolism

Acute kidney injury (AKI) has high morbidity, high mortality, and poor prognosis. The pathogenesis of AKI is complex and has not yet been fully elucidated. In recent years, studies have found that lipid metabolism disorders play an important role in the occurrence and development of AKI.

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The role of abnormal lipid metabolism in AKI

(1) Mechanism of fatty acid metabolism in renal tubular epithelial cells under physiological conditions

The kidney is a highly metabolic organ rich in mitochondria, and it requires a lot of energy to maintain its function under physiological conditions. Fatty acid oxidation (FAO) is the main source of energy for renal tubular epithelial cells. Fatty acids are mediated by lipid transporter CD36, etc., and transported to the mitochondrial matrix through CPT1 and CPT2 carnitine shuttle transmembrane, and produce energy through FAO. FAO is regulated by various epigenetic, transcriptional, and post-translational factors, such as AMPK, PGC-1α, PPARα, SIRT, etc.

(2) Mechanism of fatty acid metabolism in renal tubular epithelial cells in the state of AKI

In the state of AKI, the imbalance of lipid transport and utilization occurs, the transcriptional activity of PGC-1α and PPARα decreases, and the level of FAO decreases, which not only hinders energy production but also promotes intracellular lipid accumulation, resulting in nephrotoxicity and renal tubular epithelial cell dysfunction and necrosis. Lipid nephrotoxicity participates in the occurrence and development of AKI through mechanisms such as autophagy function defect, oxidative stress, endoplasmic reticulum stress, inflammatory response, and epigenetic modification.

The influence of abnormal lipid metabolism on the outcome of AKI: FAO disorder causes tubular epithelial cells to switch from an epithelial phenotype to a mesenchymal phenotype, resulting in remodeling of the cytoskeleton and deposition of the extracellular matrix. In addition, FAO disorder also reprograms the energy metabolism of renal tubular epithelial cells, and the energy supply switches from FAO to glycolysis to adapt to the disease environment. Metabolism reprogramming in the short term has a certain renal protective effect, but it cannot restore normal energy metabolism in the long term. Can lead to renal fibrosis.

Analysis of lipidomics in AKI

Lipidomics is the use of the principles and techniques of analytical chemistry to study lipids, reveal lipid metabolism changes in disease states, identify key biomarkers in metabolic regulation, and provide evidence for disease intervention. In recent years, the importance of lipidomics in the diagnosis and treatment of AKI has gradually attracted attention.

In the folic acid-induced AKI mouse model, lipidomics analysis found that the content of phosphatidylethanolamine (PE) in kidney tissue was significantly decreased, the content of phosphatidylinositol (PI) was significantly increased, and the ratio of PE/PI was significantly decreased. The decrease in PE content may be associated with endoplasmic reticulum stress, apoptosis, and inflammatory responses. A decrease in the PE/PI ratio reflects changes in cell membrane composition that reflect AKI disrupting membrane stability, organelle function, and cell-protein interactions. In a cisplatin-induced early mouse model of AKI, the lipidomic analysis found that ceramide (Cer) content was significantly increased in both cortex and medulla, suggesting that Cer may be involved in cisplatin induction through both intrinsic and extrinsic pathways of AKI-induced apoptosis. We performed lipidomic analysis on the plasma of patients with cardiac surgery-associated AKI (CSA-AKI), and detected a total of 65 lipids with significant differences, among which the top ten lipid molecules in the fold of variation (FC) were three Phosphatidylinositol phosphate PIP3 (24:3e), PE (27:1/14:1), PE (43:4e), PE (20:5/23:0), zymosterol ZyE (38:3), Sphingomyelin SM (t18:0/23:6), SM (t18:0/21:3), ZyE (34:4), PE (20:3e/20:3), phosphatidylinositol diphosphate PIP2 ( 4:0/18:2). KEGG analysis showed that CSA-AKI was closely related to glycerophospholipid metabolism, glyceride, and arachidonic acid metabolism pathways.

Research on targeted regulation of lipid drugs in AKI

Targeted regulation of lipid drugs for the treatment of AKI is currently in the research stage, mainly including FAO agonists, mitochondrial targeting peptides, and antioxidants. Among them, FAO agonists include PPARα agonist, PPARγ agonist, SIRT3 agonist, PGC-1α agonist, AMPK agonist, CPT-2 agonist, UCP1 agonist, etc. The other two types are mitochondrial targeting peptide SS-31 and Antioxidant MitoQ.

Fenofibrate and melatonin can upregulate genes related to FAO in mitochondria and peroxisomes by activating PPARα, thereby increasing energy production and reducing lipid accumulation. Animal experiments have found that fenofibrate and melatonin can attenuate renal damage in sepsis-associated AKI and cisplatin-induced AKI, respectively.

GW4064 is a potent small molecule agonist that can regulate PPARγ activity and increase FAO levels by activating FXR. Both in vitro and in vivo experiments found that GW4064 can protect renal tubular epithelial cells by improving mitochondrial function and reducing lipid accumulation in cisplatin-induced AKI.

HKL is a small molecular compound extracted from magnolia plants, which can directly bind to SIRT3 and enhance the functional activity of SIRT3. In the cisplatin-induced AKI mouse model, it was observed that HKL not only significantly increased the expression of SIRT3, but also up-regulated the expression of FAO-related transcription factors CPT-1α and PPARα, resulting in a significant decrease in the concentration of free fatty acids in the kidney.

ZLN005 is a synthetic small molecule compound that can promote the expression of PGC-1α, and strengthen PGC-1α/CPT-1α signal transduction in renal tubular epithelial cells, thereby enhancing FAO and reducing lipid accumulation. The study found that ZLN005 can significantly reduce the apoptosis induced by ischemia-reperfusion AKI.

C3G, a common anthocyanin, can enhance FAO by increasing AMPK phosphorylation levels. Both in vitro and in vivo experiments found that C3G can inhibit cell ferroptosis induced by ischemia-reperfusion AKI.

EP4 agonist CAY10580 enhanced FAO and macrophage lipid phagocytosis by activating CPT-2 and regulating macrophage polarization. The study found that CAY10580 can significantly reduce the degree of renal tubular swelling and interstitial fibrosis in ischemia-reperfusion AKI mice.

UCP1 agonist CL316243 reduces the inflammatory response and renal tubular cell apoptosis by causing the browning of adipose tissue, activating AMPK/ULK1 pathway-mediated autophagy. Both in vivo and in vitro experiments showed that CL316243 could significantly alleviate lipid accumulation caused by cisplatin-induced AKI.

SS-31 is a new type of mitochondria-targeted small molecular polypeptide, which can freely pass through the cell membrane and selectively gather in the inner mitochondrial membrane, and has the functions of anti-oxidative stress, inhibition of lipid peroxidation and mitochondrial permeability transition. Studies have found that SS-31 can alleviate oxidative stress and apoptosis caused by cisplatin-induced AKI, thereby alleviating renal injury.

MitoQ is a new generation of mitochondrial antioxidants. Studies have found that MitoQ can significantly reduce the level of ROS in mitochondria, thereby reducing apoptosis and playing a role in the treatment of sepsis-related AKI.

In summary, abnormal lipid metabolism plays an important role in the occurrence and development of AKI. Lipidomics analysis helps to find early diagnostic markers of AKI by revealing the changes in lipid metabolism in the state of AKI. In addition, targeting lipid metabolism may be a new direction for the treatment of AKI.