The Protective Role of Intermedin in Contrast-Induced Acute Kidney Injury: Enhancing Peritubular Capillary Endothelial Cell Adhesion and Integrity Through the cAMP/Rac1 Pathway.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Acute Kidney Injury*/chemically induced ; Acute Kidney Injury*/metabolism ; Acute Kidney Injury*/pathology ; Acute Kidney Injury*/drug therapy ; Human Umbilical Vein Endothelial Cells*/metabolism ; Human Umbilical Vein Endothelial Cells*/drug effects ; Contrast Media*/adverse effects ; rac1 GTP-Binding Protein*/metabolism ; Cyclic AMP*/metabolism ; Cell Adhesion*/drug effects ; Signal Transduction*/drug effects; Humans ; Animals ; Rats ; Adrenomedullin/pharmacology ; Adrenomedullin/metabolism ; Male ; Iohexol/adverse effects ; Rats, Sprague-Dawley ; Neuropeptides/metabolism ; Neuropeptides/pharmacology ; Disease Models, Animal ; Peptide Hormones
    • Abstract:
      Contrast-induced acute kidney injury (CIAKI) is a common complication with limited treatments. Intermedin (IMD), a peptide belonging to the calcitonin gene-related peptide family, promotes vasodilation and endothelial stability, but its role in mitigating CIAKI remains unexplored. This study investigates the protective effects of IMD in CIAKI, focusing on its mechanisms, particularly the cAMP/Rac1 signaling pathway. Human umbilical vein endothelial cells (HUVECs) were treated with iohexol to simulate kidney injury in vitro. The protective effects of IMD were assessed using CCK8 assay, flow cytometry, ELISA, and Western blotting. A CIAKI rat model was utilized to evaluate renal peritubular capillary endothelial cell injury and renal function through histopathology, immunohistochemistry, immunofluorescence, Western blotting, and transmission electron microscopy. In vitro, IMD significantly enhanced HUVEC viability and mitigated iohexol-induced toxicity by preserving intercellular adhesion junctions and activating the cAMP/Rac1 pathway, with Rac1 inhibition attenuating these protective effects. In vivo, CIAKI caused severe damage to peritubular capillary endothelial cell junctions, impairing renal function. IMD treatment markedly improved renal function, an effect negated by Rac1 inhibition. IMD protects against renal injury in CIAKI by activating the cAMP/Rac1 pathway, preserving peritubular capillary endothelial integrity and alleviating acute renal injury from contrast media. These findings suggest that IMD has therapeutic potential in CIAKI and highlight the cAMP/Rac1 pathway as a promising target for preventing contrast-induced acute kidney injury in at-risk patients, ultimately improving clinical outcomes.
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    • Grant Information:
      81870354 National Natural Science Foundation of China; YDZJSX2021C026 Shanxi Province Central Leading Local Science and Technology Development Fund Project; 201901D211492 The Science and Technology Department of Shanxi Province
    • Contributed Indexing:
      Keywords: Rac1; cAMP; contrast media; contrast-induced acute kidney injury; endothelial barrier; intermedin; peritubular capillaries
    • Accession Number:
      0 (Contrast Media)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
      E0399OZS9N (Cyclic AMP)
      148498-78-6 (Adrenomedullin)
      4419T9MX03 (Iohexol)
      0 (ADM2 protein, human)
      0 (Neuropeptides)
      0 (Peptide Hormones)
    • Publication Date:
      Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241105
    • Publication Date:
      20241106
    • Accession Number:
      PMC11508126
    • Accession Number:
      10.3390/ijms252011110
    • Accession Number:
      39456892