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Background <p>Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in patients with severe health conditions, yet effective targeted therapies are still not available. Recent studies implicate impaired fatty acid oxidation (FAO) and metabolic dysregulation in its pathogenesis. A clinically approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist, fenofibrate, may improve energy metabolism and enhance renal FAO. This study investigated whether fenofibrate mitigates SA-AKI by restoring renal FAO and mitochondrial function.</p> Methods <p>The three groups (<i>n</i> = 6 per group) were as follows: control, lipopolysaccharide (LPS)-induced SA-AKI, and LPS with fenofibrate pretreatment (0.2% dietary supplementation for 7 days), with male C57BL/6 mice used for the study. Kidney injury was induced by intraperitoneal LPS injection (10 mg/kg). After 24 hours, renal function (serum creatinine [Scr] and blood urea nitrogen [BUN]), inflammation (interleukin-1 beta [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α]), and histopathology were evaluated. Biomarkers of kidney injury, including kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as indicators of energy metabolism (adenosine triphosphate [ATP]) and lipid accumulation (triglycerides, glycerol, non-esterified fatty acids [NEFA]), were assessed. Mitochondrial function (citrate synthase), FAO capacity, and expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), PPARα, carnitine palmitoyltransferase 1A (CPT1A), CPT2, and acyl-CoA oxidase 1 (ACOX1) were assessed.</p> Results <p>Fenofibrate markedly enhanced renal function, lowered levels of Scr and BUN, decreased proinflammatory cytokines, and inhibited the expression of KIM-1 and NGAL. Histological damage was alleviated, and Oil Red O staining revealed reduced lipid accumulation. ATP levels and citrate synthase activity were restored, while renal levels of triglycerides, glycerol, and NEFA were decreased. Fenofibrate increased the expression of genes and proteins associated with FAO and restored the AMPK–PGC1α–PPARα signaling pathway.</p> Conclusions <p>Fenofibrate attenuates SA-AKI by enhancing renal FAO and mitochondrial energy metabolism via the AMPK–PGC1α–PPARα pathway, supporting its potential as a metabolic therapy for SA-AKI.</p>

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Fenofibrate alleviates sepsis-associated acute kidney injury by enhancing renal fatty acid oxidation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Siyao Zeng,
  • Jingkai Wang,
  • Chumming Guan,
  • Zhipeng Yao,
  • Yu Zhang,
  • Yue Li,
  • Junbo Zheng,
  • Hongliang Wang

摘要

Background

Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in patients with severe health conditions, yet effective targeted therapies are still not available. Recent studies implicate impaired fatty acid oxidation (FAO) and metabolic dysregulation in its pathogenesis. A clinically approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist, fenofibrate, may improve energy metabolism and enhance renal FAO. This study investigated whether fenofibrate mitigates SA-AKI by restoring renal FAO and mitochondrial function.

Methods

The three groups (n = 6 per group) were as follows: control, lipopolysaccharide (LPS)-induced SA-AKI, and LPS with fenofibrate pretreatment (0.2% dietary supplementation for 7 days), with male C57BL/6 mice used for the study. Kidney injury was induced by intraperitoneal LPS injection (10 mg/kg). After 24 hours, renal function (serum creatinine [Scr] and blood urea nitrogen [BUN]), inflammation (interleukin-1 beta [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α]), and histopathology were evaluated. Biomarkers of kidney injury, including kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as indicators of energy metabolism (adenosine triphosphate [ATP]) and lipid accumulation (triglycerides, glycerol, non-esterified fatty acids [NEFA]), were assessed. Mitochondrial function (citrate synthase), FAO capacity, and expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), PPARα, carnitine palmitoyltransferase 1A (CPT1A), CPT2, and acyl-CoA oxidase 1 (ACOX1) were assessed.

Results

Fenofibrate markedly enhanced renal function, lowered levels of Scr and BUN, decreased proinflammatory cytokines, and inhibited the expression of KIM-1 and NGAL. Histological damage was alleviated, and Oil Red O staining revealed reduced lipid accumulation. ATP levels and citrate synthase activity were restored, while renal levels of triglycerides, glycerol, and NEFA were decreased. Fenofibrate increased the expression of genes and proteins associated with FAO and restored the AMPK–PGC1α–PPARα signaling pathway.

Conclusions

Fenofibrate attenuates SA-AKI by enhancing renal FAO and mitochondrial energy metabolism via the AMPK–PGC1α–PPARα pathway, supporting its potential as a metabolic therapy for SA-AKI.