Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury
Arthur Lau, … , Craig N. Jenne, Daniel A. Muruve
Arthur Lau, … , Craig N. Jenne, Daniel A. Muruve
Published June 4, 2018
Citation Information: J Clin Invest. 2018;128(7):2894-2913. https://doi.org/10.1172/JCI96640.
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Research Article Inflammation Nephrology

Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury

Abstract

Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3–deficient (Nlrp3-deficient) mice displayed reduced epithelial cell injury and inflammation in the kidney in a model of contrast-induced AKI (CI-AKI). Unexpectedly, contrast agents directly induced tubular epithelial cell death in vitro that was not dependent on Nlrp3. Rather, contrast agents activated the canonical Nlrp3 inflammasome in macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes in perivascular CX3CR1+ resident phagocytes in the kidney. Following rapid filtration into the tubular luminal space, DTA was reabsorbed and concentrated in tubular epithelial cells via the brush border enzyme dipeptidase-1 in volume-depleted but not euvolemic mice. LysM-GFP+ macrophages recruited to the kidney interstitial space ingested contrast material transported from the urine via direct interactions with tubules. CI-AKI was dependent on resident renal phagocytes, IL-1, leukocyte recruitment, and dipeptidase-1. Levels of the inflammasome-related urinary biomarkers IL-18 and caspase-1 were increased immediately following contrast administration in patients undergoing coronary angiography, consistent with the acute renal effects observed in mice. Taken together, these data show that CI-AKI is a multistep process that involves immune surveillance by resident and infiltrating renal phagocytes, Nlrp3-dependent inflammation, and the tubular reabsorption of contrast via dipeptidase-1.

Authors

Arthur Lau, Hyunjae Chung, Takanori Komada, Jaye M. Platnich, Christina F. Sandall, Saurav Roy Choudhury, Justin Chun, Victor Naumenko, Bas G.J. Surewaard, Michelle C. Nelson, Annegret Ulke-Lemée, Paul L. Beck, Hallgrimur Benediktsson, Anthony M. Jevnikar, Sarah L. Snelgrove, Michael J. Hickey, Donna L. Senger, Matthew T. James, Justin A. Macdonald, Paul Kubes, Craig N. Jenne, Daniel A. Muruve

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Figure 7

Contrast uptake by monocytes in the kidney.

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Contrast uptake by monocytes in the kidney. Mice were treated with CF568...
Mice were treated with CF568-labeled DTA for 1 hour before kidney leukocytes were sorted using CD11b and analyzed by flow cytometry. Monocytes/macrophages identified using CX3CR1, Ly6C, and F4/80 were analyzed for DTA uptake. Inhibitor studies using anti–ICAM-1 and D-4F peptide in mice before DTA treatment were also analyzed using flow cytometry. Images are representative of 3 independent experiments.