Increased transforming growth factor beta (TGF-\u03b2) and pSMAD3 signaling in a Murine Model for Contrast Induced Kidney Injury

Sreenivasulu Kilari,Deborah L Mccall,Binxia Yang,Amit Sharma,Sanjay Misra

doi:10.1038/s41598-018-24340-z

Sreenivasulu Kilari, Deborah L Mccall + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-24340-z

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Abstract

We tested the hypothesis that post-contrast acute kidney injury (PC-AKI) occurs due to increase in transforming growth factor beta (Tgf-β) and pSMAD3 signaling in a murine model of PC-AKI. Mice had nephrectomy performed and twenty-eight days later, 100-μL of radio-contrast (Vispaque 320) or saline was administered via the jugular vein. Animals were sacrificed at 2, 7, and 28 days later and the serum BUN, creatinine, urine protein levels, and kidney weights were assessed. In human kidney-2 (HK-2) cells, gene and protein expression with cellular function was assessed following inhibition of TGFβR-1 plus contrast exposure. After contrast administration, the average serum creatinine is significantly elevated at all time points. The average gene expression of connective tissue growth factor (Ctgf), Tgfβ-1, matrix metalloproteinase-9 (Mmp-9), and collagen IVa (Col IVa) are significantly increased at 2 days after contrast administration (P < 0.05). Cellular proliferation is decreased and there is increased apoptosis with tubulointerstitial fibrosis. Contrast administered to HK-2 cells results in increased pSMAD3 levels and gene expression of Ctgf, Tgfβ-1, Tgfβ-2, Col IVa, Mmp-9, and caspase/7 activity with a decrease in proliferation (all, P < 0.05). TGFβR-1 inhibition decreased the expression of contrast mediated pro-fibrotic genes in HK-2 cells with no change in the proliferation and apoptosis.

Highlights

The most common cause of iatrogenic acute kidney injury is post-contrast acute kidney injury (PC-AKI), which occurs when patients receive iodinated contrast after an imaging study such as a computed tomographic or angiogram[1,2]
Since tubular damage is found in patients with PC-AKI, we assessed the in vitro effects of contrast exposure upon human kidney-2 (HK-2) cells by determining the gene expression of Tgfβ-1, Tgfβ-2, connective tissue growth factor (Ctgf), matrix metalloproteinase-9 (Mmp-9), and collagen IVa (Col IVa) with cell proliferation and apoptosis
We identified that Tgfβ-1/pSMAD3 signaling is up regulated with Ctgf, Mmp-9, and Col-IVa gene expression, increase in fibrosis and a decrease in proliferation

Summary

Introduction

The most common cause of iatrogenic acute kidney injury is post-contrast acute kidney injury (PC-AKI), which occurs when patients receive iodinated contrast after an imaging study such as a computed tomographic or angiogram[1,2]. This results in impaired kidney function and 30% of the patients may require renal replacement therapy or alternative support until the kidney function improves[3,4,5,6,7,8,9]. We inhibited TGFβR-1 and evaluated the effects on gene expression and cell function after contrast exposure using HK-2 cells

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