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 3

Contrast cytotoxicity in renal TECs.

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Contrast cytotoxicity in renal TECs. (A and B) Cell death was determined...
(A and B) Cell death was determined in HPTCs using MTT assay after treatment with various dilutions of ioversol in culture medium (1:1 to 1:8) (vs. no treatment [NT]), 1:1: ***P < 0.001, 1:2: ***P < 0.001, 1:4: *P = 0.03, 1:8: *P = 0.03, n = 9–12/group, ANOVA) or DTA (1:1 to 1:64) (vs. NT, 1:1: **P = 0.008, 1:2: **P = 0.009, 1:4:**P = 0.009, 1:8: **P = 0.009, n = 9–12/group vs. NT, ANOVA). (C) HPTCs were treated with PBS control or ioversol and labeled with propidium iodide to identify necrotic cells for 24 hours. Images were captured and analyzed for necrotic cells with the IncuCyte Live Cell Analysis System (n = 4/group). (D) Cell death in ioversol-treated HPTCs with pan-caspase (zVAD) or caspase-8 (IETD) inhibitors (MTT assay, P = NS, n = 6–12/group, ANOVA). (E) TECs isolated from Nlrp3+/+ or Nlrp3–/– mice were treated with ioversol, DTA, or hyperosmolar mannitol buffer (700 mOsm) (M-700). Cell death was measured by MTT assay (P = NS, n = 4/group, ANOVA).