Regulation Of Pericyte Metabolic Reprogramming Inhibits The Progression Of AKI To CKD

Acute kidney injury (Acute Kidney Injury, AKI) is often accompanied by high morbidity and mortality and is a long-term risk factor for the development of Chronic Kidney Disease (CKD). Interstitial fibrosis and proliferation of myofibroblasts are typical pathological features of AKI progressing to CKD. Pericytes are the major source of myofibroblasts in renal fibrosis. However, the mechanisms underlying pericyte-to-myofibroblast transition (PMT) remain unclear. Academician Chen Xiangmei's team from PLA General Hospital found that fatty acid oxidation was down-regulated and glycolysis was up-regulated during PMT.

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In addition, PGClα activator ZLN-005 can activate FAO or hexokinase 2 (hexokinase 2, HK2) inhibitor 2-DG to inhibit glycolysis, both of which can inhibit PMT and delay the progression of AKI to CKD. Mechanistically, AMPK is an upstream molecule that regulates the conversion of glycolysis to FAO metabolism; specifically, it promotes FAO by activating the expression of PGClα-CPT1A and inhibits glycolysis by inhibiting the expression of HIF1α-HK2, thereby inhibiting PMT.

1. In AKI-CKD, pericytes transdifferentiate into myofibroblast pericytes, which are mesenchymal-derived cells that mainly express platelet-derived growth factor (PDGFR-β), chondroitin sulfate proteoglycan (NG2) and Cell surface glycoprotein (CD146). The results of immunofluorescence colocalization showed that in AKI-CKD, PDGFR-β+α-SMA+, CD146+α-SMA+, and NG2+α-SMA+ cells were significantly increased, and pericytes were transdifferentiated into myofibroblasts.

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2. In AKI-CKD, the FAO of pericytes is impaired and the level of glycolysis is increased. Next, to clarify the mechanism of pericyte transdifferentiation in AKI-CKD, the author sorted Sham, uIRI-2d, uIRI-7d, and uIRI-14d PDGFR-β+ pericytes and were subjected to transcriptome sequencing. The results of GSEA analysis showed that in AKI-CKD, the signaling pathways related to fatty acid oxidation of PDGFR-β+ pericytes, Mitochondrial fatty acid beta-oxidation, and fatty acid metabolism, were significantly down-regulated. Glycolysis-related genes were significantly up-regulated.

In addition, the authors further confirmed the results of transcriptome sequencing by qPCR and immunofluorescence co-staining. The authors found that in AKI-CKD, the expression of fatty acid oxidation transcription factor PGC1α in NG2+ pericytes was significantly decreased and the expression of glycolytic key enzyme HK2 was significantly increased.

3. PGC1α activator ZLN-00 increases FAO and inhibits pericyte transdifferentiation To further clarify the role of fatty acid oxidation in pericyte transdifferentiation, the author gave PGC1α activator ZLN-005 and then sorted out ZLN-005 treatment After 7 days and 14 days, PDGFR-β+ pericytes were analyzed by transcriptome sequencing. The author found that after 7 days and 14 days of PGC1α activator ZLN-005, the signaling pathways related to fatty acid oxidation in PDGFR-β+ pericytes, Mitochondrial fatty acid beta-oxidation, and fatty acid metabolism, were significantly up-regulated, and fibrosis-related pathways were significantly up-regulated. down.

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In addition, the authors further confirmed the results of transcriptome sequencing with qPCR and immunofluorescence co-staining. The authors found that ZLN-005 could significantly increase the expression of PGC1α in NG2+ pericytes, increase the level of FAO in pericytes, and reduce renal lipid deposition.

4. HK2 inhibitor 2-DG inhibits glycolysis and pericyte transdifferentiation To further clarify the role of glycolysis in pericyte transdifferentiation, the author gave glycolysis key enzyme HK2 inhibitor 2-DG and sorted Transcriptome sequencing was performed on PDGFR-β+ pericytes administered for 7 and 14 days.

The authors found that glycolysis-related genes and fibrosis-related genes were significantly reduced after 7 and 14 days of 2-DG treatment. In addition, the authors further validated the results of transcriptome sequencing. The authors found that 2-DG could significantly inhibit the expression of HK2 in NG2+ pericytes and inhibit the uIRI-induced increase in pericyte glycolysis.

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5. AMPK is a key upstream molecule that regulates the conversion of pericyte glycolysis to FAO. AMPK plays an important role in the regulation of cellular energy homeostasis. Studies have shown that in AKI-CKD, AMPK regulates the occurrence of renal fibrosis. The authors further explored whether AMPK is involved in the metabolic reprogramming of pericytes. It was shown that AMPK regulates the expression of PGC1α/CPT1A in pericytes, increases FAO, and at the same time inhibits the expression of HIF1α/HK2 in pericytes and inhibits glycolysis.

The Mechanism of Cistanche Treatment Kidney disease

Cistanche is a traditional herb commonly used in China for the treatment of kidney disease, especially kidney deficiency syndrome. Cistanche contains various bioactive compounds, including phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which exert multiple pharmacological activities, such as anti-inflammatory, anti-oxidative, and immunomodulatory effects.

The mechanism of Cistanche in treating kidney disease involves several aspects:

Improving renal hemodynamics: Cistanche can increase renal blood flow and improve glomerular filtration rate (GFR), thereby improving kidney function.

Reducing oxidative stress: Cistanche contains potent antioxidant compounds that can scavenge free radicals and reduce oxidative stress, which is a critical factor in the onset and progression of kidney disease.

Inhibiting inflammation: Cistanche can suppress the release of inflammatory cytokines and chemokines, which can reduce inflammation in the kidney and prevent further damage.

Protecting renal cells: Cistanche can protect renal cells from damage caused by various factors such as toxins, ischemia/reperfusion injury, and aging.

Modulating the immune system: Cistanche can regulate the immune system and enhance the body's defense against infection and inflammation.

Overall, Cistanche can improve kidney function and reduce the progression of kidney disease due to its beneficial effects on renal hemodynamics, oxidative stress, inflammation, renal cell protection, and immune modulation.