Increased fibrotic signaling in a murine model for intra-arterial contrast-induced acute kidney injury

Amit Sharma, Sreenivasulu Kilari, Chuanqi Cai, Michael L. Simeon, Sanjay Misra

Research output: Contribution to journalArticle

Abstract

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem, and more than 70 million patients undergo studies using iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present article was to determine the role of transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (SMAD)3 and associated collagen expression in a murine model of intra-arterial CI-AKI. The murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease. Twenty-eight days later, 100 μL of contrast agent [iodixanol (320 mg/mL)] or saline were administered via the carotid artery. Two days after contrast administration, compared with saline, average serum creatinine was significantly elevated (P ≤ 0.05). In the cortex, there was a significant increase in phosphorylated SMAD3 and gene expression of TGF-β1, TGF-β receptor type I, and TGF-β receptor type II at day 2 in the contrast group compared with the saline group. Average gene expressions of connective tissue growth factor, matrix metalloproteinase-2 and -9, and collagen type I-α and type IV-α were significantly increased at 2 days after contrast administration (all P < 0.05). Moreover, there was a decrease in Ki-67 staining in the cortex, with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling in the cortex and medulla after contrast administration (P < 0.05). In the murine intra-arterial CI-AKI model, there was increased hypoxia and TGF-β1/SMAD3 pathway activation and collagen expression, resulting in renal fibrosis. Together, these results suggest that the TGF-β1/SMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.

Original languageEnglish (US)
Pages (from-to)F1210-F1219
JournalAmerican Journal of Physiology - Renal Physiology
Volume318
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • Animal models
  • Contrast
  • Creatinine
  • Kidney
  • Kidney injury molecule-1
  • Postcontrast acute kidney injury
  • Transforming growth factor-β/ SMAD3 signaling

ASJC Scopus subject areas

  • Physiology
  • Urology

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