Increased fibrotic signaling in a murine model for intra-arterial contrast induced acute kidney Injury (CI-AKI).

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem and more than 70 million patients undergo studies utilizing iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present paper was to determine the role of tissue growth factor-beta1 (TGF-beta1)/ mothers against decapentaplegic homolog 3 (SMAD3) signaling and associated collagen expression in a murine model of intraarterial CI-AKI. Murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease (CKD). Twenty-eight days later, 100muLof contrast agent (Iodixanol 320mgl/ml) or saline was administered via the carotid artery. Two days later, after contrast administration when compared to saline, the average serum creatinine was significantly elevated (P<0.05). In the cortex, there was a significant increase in the expression of pSMAD3 and gene expression of TGF-beta1, TGFbetaR1 and TGFbetaR2 at day 2 in contrast group compared to saline group. The average gene expression of connective tissue growth factor (Ctgf), matrix metalloproteinase (MMP)-2, -9, collagen (Col) -Ia, and -IVa 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 increase in TUNEL 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-beta1/pSMAD3 pathway activation and collagen expression resulting in renal fibrosis. Together these results suggest TGF-beta1/pSMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.