Chemerin attenuates acute kidney injury by inhibiting ferroptosis via the AMPK/NRF2/SLC7A11 axis

Commun Biol. 2024 Dec 19;7(1):1679. doi: 10.1038/s42003-024-07377-x.

Abstract

Acute kidney injury (AKI) is a common and life-threatening condition associated with cell death, where ferroptosis plays a critical role. Chemerin, primarily produced in white adipose tissue, has multiple biological functions in renal pathophysiology. However, to date, whether and how chemerin regulates the progression of AKI remain unclear. Here, we found that chemerin expression was reduced in both AKI model mice and cells. Similarly, serum chemerin levels were also decreased in AKI patients. The administration of recombinant chemerin improves renal function in ischemia-reperfusion (I/R) model mice. Chemerin significantly attenuates ferroptosis in kidneys. In TCMK-1 cells, chemerin knockdown further aggravates ferroptosis. Mechanistically, chemerin activates AMP-activated protein kinase (AMPK), which induces the phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2) in renal tubular cells. Subsequently, NRF2 translocates into the nucleus, where it stimulates the expression of cystine/glutamate antiporter solute carrier (SLC7A11). As a result, cystine uptake and glutathione (GSH) biosynthesis in renal tubular cells were increased, which confers cells with higher capacity against ferroptosis. Overall, our findings indicate that chemerin plays a protective role in AKI by repressing ferroptosis in renal tubular cells, which is likely due to the activation in the AMPK/NRF2/SLC7A11 axis.

MeSH terms

  • AMP-Activated Protein Kinases* / metabolism
  • Acute Kidney Injury* / metabolism
  • Acute Kidney Injury* / pathology
  • Amino Acid Transport System y+* / genetics
  • Amino Acid Transport System y+* / metabolism
  • Animals
  • Chemokines* / genetics
  • Chemokines* / metabolism
  • Disease Models, Animal
  • Ferroptosis* / drug effects
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2* / genetics
  • NF-E2-Related Factor 2* / metabolism
  • Signal Transduction

Substances

  • Chemokines
  • NF-E2-Related Factor 2
  • AMP-Activated Protein Kinases
  • Amino Acid Transport System y+
  • Slc7a11 protein, mouse
  • chemerin protein, mouse
  • Nfe2l2 protein, mouse
  • SLC7A11 protein, human
  • RARRES2 protein, human
  • Intercellular Signaling Peptides and Proteins