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 2

Contrast induces Nlrp3-dependent leukocyte recruitment to the kidney.

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Contrast induces Nlrp3-dependent leukocyte recruitment to the kidney. (A...
(A) LysM(gfp/gfp) and Nlrp3–/– LysM(gfp/gfp) mice were treated with vehicle or ioversol and assessed at 6 hours, 1 day, and 3 days using multiphoton intravital microscopy. Capillaries and injured/necrotic cells were labeled with Qtracker and SYTOX, respectively. Tubules are visualized by autofluorescence. Image is representative of 3 independent experiments. Scale bars: 100 μm. (B) Quantification of stationary GFP+ cells per field (Nlrp3+/+ vs. Nlrp3–/–, 6 hours: **P = 0.003, day 1: **P = 0.002, day 3: *P = 0.02, n = 6–9/group, ANOVA). (C and D) LysM(gfp/gfp) mice were treated with vehicle or ioversol, and LysM-GFP+ leukocytes were sorted from total kidney tissue and analyzed by flow cytometry for CD11b, CX3CR1, F4/80, Ly6G, and Ly6C at 6 hours. Renal infiltrating neutrophils (Nlrp3+/+, vehicle vs. ioversol, **P = 0.005, n = 3/group, 2-tailed Student’s t test) and monocytes (Nlrp3+/+, vehicle vs. ioversol, **P = 0.002, n = 3/group, 2-tailed Student’s t test) were quantified in ioversol-treated Nlrp3+/+ and Nlrp3–/– mice at 6 hours by flow cytometry. (E and F) F4/80 immunofluorescence (confocal microscopy) and quantification in kidneys from Nlrp3+/+ and Nlrp3–/– mice treated with vehicle or ioversol on day 3 (Nlrp3+/+ vs. Nlrp3–/–, day 3: ***P < 0.001, n = 3–5/group, 2-tailed Student’s t test). Scale bars: 200 μm.