Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition

Chen, Xu; Hong, Quan; Zhuang, Kaiting; Ren, Xuejing; Cui, Shaoyuan; Dong, Zheyi; Wang, Qian; Bai, Xueyuan; Chen, Xiangmei

doi:10.1016/j.metabol.2023.155592

Cited by 8 publications

(4 citation statements)

References 50 publications

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“…Moreover, our previous study has provided evidence of PDGFRβ expression in the kidneys of human CKD patients. 14 …”

Section: Resultsmentioning

confidence: 99%

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

Chen,

Bai,

Chen

et al. 2023

Cell Proliferation

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We aimed to investigate the role of renal pericyte pyruvate kinase M2 (PKM2) in the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). The role of PKM2 in renal pericyte‐myofibroblast transdifferentiation was investigated in an AKI‐CKD mouse model. Platelet growth factor receptor beta (PDGFRβ)‐iCreERT2; tdTomato mice were used for renal pericyte tracing. Western blotting and immunofluorescence staining were used to examine protein expression. An 5‐ethynyl‐2′‐deoxyuridine assay was used to measure renal pericyte proliferation. A scratch cell migration assay was used to analyse cell migration. Seahorse experiments were used to examine glycolytic rates. Enzyme‐linked immunoassay was used to measure pyruvate kinase enzymatic activity and lactate concentrations. The PKM2 nuclear translocation inhibitors Shikonin and TEPP‐46 were used to alter pericyte transdifferentiation. In AKI‐CKD, renal pericytes proliferated and transdifferentiated into myofibroblasts and PKM2 is highly expressed in renal pericytes. Shikonin and TEPP‐46 inhibited pericyte proliferation, migration, and pericyte‐myofibroblast transdifferentiation by reducing nuclear PKM2 entry. In the nucleus, PKM2 promoted downstream lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) transcription, which are critical for glycolysis. Therefore, PKM2 regulates pericyte glycolytic and lactate production, which regulates renal pericyte‐myofibroblast transdifferentiation. PKM2‐regulated renal pericyte‐myofibroblast transdifferentiation by regulating downstream LDHA and GLUT1 transcription and lactate production. Reducing nuclear PKM2 import can reduce renal pericytes‐myofibroblasts transdifferentiation, providing new ideas for AKI‐CKD treatment.

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“…Moreover, our previous study has provided evidence of PDGFRβ expression in the kidneys of human CKD patients. 14 …”

Section: Resultsmentioning

confidence: 99%

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

Chen,

Bai,

Chen

et al. 2023

Cell Proliferation

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“…Unilateral ischemic acute kidney injury (AKI) or chronic kidney disease (CKD) mouse models were established by clamping the left renal artery. Unilateral renal ischemia-reperfusion was performed as recently described ( 7 , 11 ). Briefly, mice were anesthetized by intraperitoneal injection of pentobarbital (60 mg/kg) prior to surgery.…”

Section: Methodsmentioning

confidence: 99%

“…Severe AKI injuries lead to abnormal repair of tubular cells, resulting in the production and secretion of various cytokines, growth factors, pro-inflammatory molecules, and pro-fibrotic molecules ( 10 ). The increased bioactive molecules play a role in both autocrine function, which is necessary for the de-differentiation, migration, and proliferation of tubular cells during regeneration ( 10 , 11 ), and in normal paracrine function, for recruiting leukocytes from circulation and activating fibroblasts and other interstitial cells ( 11 , 12 ). The characteristics of activated fibroblasts include elevated expression of contractile proteins, increased cell motility, induction of pro-inflammatory genes, and high-level deposition of collagen and other ECM proteins ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Flavin containing monooxygenase 2 regulates renal tubular cell fibrosis and paracrine secretion via SMURF2 in AKI‑CKD transformation

Wang,

Zha,

Huang

et al. 2023

Int J Mol Med

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In the follow-up of hospitalized patients with acute kidney injury (AKI), it has been observed that 15-30% of these patients progress to develop chronic kidney disease (CKD). Impaired adaptive repair of the kidneys following AKI is a fundamental pathophysiological mechanism underlying renal fibrosis and the progression to CKD. Deficient repair of proximal tubular epithelial cells is a key factor in the progression from AKI to CKD. However, the molecular mechanisms involved in the regulation of fibrotic factor paracrine secretion by injured tubular cells remain incompletely understood. Transcriptome analysis and an ischemia-reperfusion injury (IRI) model were used to identify the contribution of flavin-containing monooxygenase 2 (FMO2) in AKI-CKD. Lentivirus-mediated overexpression of FMO2 was performed in mice. Functional experiments were conducted using TGF-β-induced tubular cell fibrogenesis and paracrine pro-fibrotic factor secretion. Expression of FMO2 attenuated kidney injury induced by renal IRI, renal fibrosis, and immune cell infiltration into the kidneys. Overexpression of FMO2 not only effectively blocked TGF secretion in tubular cell fibrogenesis but also inhibited aberrant paracrine activation of pro-fibrotic factors present in fibroblasts. FMO2 negatively regulated TGF-β-mediated SMAD2/3 activation by promoting the expression of SMAD ubiquitination regulatory factor 2 (SMURF2) and its nuclear translocation. During the transition from AKI to CKD, FMO2 modulated tubular cell fibrogenesis and paracrine secretion through SMURF2, thereby affecting the outcome of the disease.

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“…These results are consistent with studies in AKI animal models obtained by IRI. Researchers have observed increased expression of the pyruvate kinase M2 subtype (PKM2) in renal-damaged PCs, suggesting that glycolysis is a pivotal metabolic pathway for PTM [68]. Therefore, targeting PC metabolic reprogramming during the AKI to CKD transition can prevent PTM, as stated by Xu et al They showed that the enhancement of fatty acid oxidation or the inhibition of the glycolytic pathway during renal IRI in an animal model can influence the fate of PC transdifferentiation and prevent the progression of the damage [69].…”

Section: Ischemia-reperfusion Injury and Pericytesmentioning

confidence: 99%

Hypoxic Inducible Factor Stabilization in Pericytes beyond Erythropoietin Production: The Good and the Bad

Troise,

Infante,

Mercuri

et al. 2024

Antioxidants

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The paracrine signaling pathways for the crosstalk between pericytes and endothelial cells are essential for the coordination of cell responses to challenges such as hypoxia in both healthy individuals and pathological conditions. Ischemia–reperfusion injury (IRI), one of the causes of cellular dysfunction and death, is associated with increased expression of genes involved in cellular adaptation to a hypoxic environment. Hypoxic inducible factors (HIFs) have a central role in the response to processes initiated by IRI not only linked to erythropoietin production but also because of their participation in inflammation, angiogenesis, metabolic adaptation, and fibrosis. While pericytes have an essential physiological function in erythropoietin production, a lesser-known role of HIF stabilization during IRI is that pericytes’ HIF expression could influence vascular remodeling, cell loss and organ fibrosis. Better knowledge of mechanisms that control functions and consequences of HIF stabilization in pericytes beyond erythropoietin production is advisable for the development of therapeutic strategies to influence disease progression and improve treatments. Thus, in this review, we discuss the dual roles—for good or bad—of HIF stabilization during IRI, focusing on pericytes, and consequences in particular for the kidneys.

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Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition

Cited by 8 publications

References 50 publications

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease

Flavin containing monooxygenase 2 regulates renal tubular cell fibrosis and paracrine secretion via SMURF2 in AKI‑CKD transformation

Hypoxic Inducible Factor Stabilization in Pericytes beyond Erythropoietin Production: The Good and the Bad

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