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 July 2, 2018; First 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 5

Contrast uptake and reabsorption in the kidney.

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Contrast uptake and reabsorption in the kidney. (A) LysM(gfp/gfp) mice w...
(A) LysM(gfp/gfp) mice were injected with CF568- labeled DTA (DTA568) and imaged with multiphoton intravital microscopy. Upper panels: hydrated mice (i.v. normal saline); lower panels: volume-depleted mice. Capillaries were labeled with Qtracker, and tubules are visualized by autofluorescence. Images are representative of 3 independent experiments. Scale bars: 100 μm. (B) Hydrated CX3CR1(gfp/+) mice were treated with CF568-labeled DTA and imaged with multiphoton intravital microscopy. 3D reconstruction (Z-stack) of DTA uptake in CX3CR1+ resident phagocytes over 10 minutes. Images are representative of 3 independent experiments. Scale bars: 20 μm. (C) Tubular uptake of DTA in volume-depleted CX3CR1(gfp/+) mice over 40 minutes by multiphoton intravital microscopy. Images are representative of 3 independent experiments. Scale bars: 100 μm. (D) 3D reconstruction (Z-stack) of DTA uptake in CX3CR1+ resident phagocytes in volume-depleted mice at 40 minutes. Images are representative of 3 independent experiments. Scale bar: 20 μm. (E) Mice were volume depleted and treated with CF568-labeled DTA for 1 hour, and contrast uptake was analyzed by flow cytometry in resident phagocytes (CD45+CX3CR1+DTA+ and CD45+CX3CR1+CD11c+DTA+). Images are representative of 3 independent experiments.