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 10

Renal DPEP-1 mediates tubular uptake of contrast from the urine.

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Renal DPEP-1 mediates tubular uptake of contrast from the urine. (A and ...
(A and B) Contrast uptake (internalization) was imaged and quantified in human renal proximal TECs (HPTCs) using CF568-labeled DTA. PNGaseF was used to de-glycosylate DPEP-1 on HPTCs as a negative control. Scale bars: 10 μm. NT vs. CF568-DTA, ***P = 0.001, n = 9–14/group, ANOVA. (C) WT mice were treated with cilastatin prior to administration of CF568-DTA, and kidneys were imaged by multiphoton intravital microscopy over 40 minutes. Capillaries were labeled with Qtracker, and tubules are visualized by autofluorescence. Images are representative of 3 independent experiments. Scale bars: 100 μm. (D and E) LysM(gfp/gfp) mice were treated with cilastatin (25 mg/kg) or vehicle control prior to administration of ioversol, and kidneys were imaged by multiphoton intravital microscopy. Scale bars: 100 μm. Inflammation was quantified by manual counting of stationary GFP+ leukocytes (saline vs. cilastatin, *P = 0.02, n = 3/group, 2-tailed Student’s t test). (F and G) WT C57BL/6 mice were treated with cilastatin or normal saline vehicle prior to ioversol administration. Urine output and serum creatinine as a measure of kidney function was determined on days 1 and 3 after contrast treatment (ref. values 0.04–0.08 mg/dl) (saline vs. cilastatin, creatinine day 3, **P = 0.003, n = 4/group, 2-tailed Student’s t test).