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

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 & 2 others Craig N. Jenne, Daniel A. Muruve

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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 CX 3 CR1+ 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.

Original languageEnglish
Pages (from-to)2894-2913
Number of pages20
JournalJournal of Clinical Investigation
Volume128
Issue number7
DOIs
Publication statusPublished - 2 Jul 2018

Cite this

Lau, A., Chung, H., Komada, T., Platnich, J. M., Sandall, C. F., Choudhury, S. R., ... Muruve, D. A. (2018). Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury. Journal of Clinical Investigation, 128(7), 2894-2913. https://doi.org/10.1172/JCI96640
Lau, Arthur ; Chung, Hyunjae ; Komada, Takanori ; Platnich, Jaye M. ; Sandall, Christina F. ; Choudhury, Saurav Roy ; Chun, Justin ; Naumenko, Victor ; Surewaard, Bas G.J. ; Nelson, Michelle C. ; Ulke-Lemée, Annegret ; Beck, Paul L. ; Benediktsson, Hallgrimur ; Jevnikar, Anthony M. ; Snelgrove, Sarah L. ; Hickey, Michael J. ; Senger, Donna L. ; James, Matthew T. ; Macdonald, Justin A. ; Kubes, Paul ; Jenne, Craig N. ; Muruve, Daniel A. / Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 7. pp. 2894-2913.
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title = "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 CX 3 CR1+ 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.",
author = "Arthur Lau and Hyunjae Chung and Takanori Komada and Platnich, {Jaye M.} and Sandall, {Christina F.} and Choudhury, {Saurav Roy} and Justin Chun and Victor Naumenko and Surewaard, {Bas G.J.} and Nelson, {Michelle C.} and Annegret Ulke-Lem{\'e}e and Beck, {Paul L.} and Hallgrimur Benediktsson and Jevnikar, {Anthony M.} and Snelgrove, {Sarah L.} and Hickey, {Michael J.} and Senger, {Donna L.} and James, {Matthew T.} and Macdonald, {Justin A.} and Paul Kubes and Jenne, {Craig N.} and Muruve, {Daniel A.}",
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Lau, A, Chung, H, Komada, T, Platnich, JM, Sandall, CF, Choudhury, SR, Chun, J, Naumenko, V, Surewaard, BGJ, Nelson, MC, Ulke-Lemée, A, Beck, PL, Benediktsson, H, Jevnikar, AM, Snelgrove, SL, Hickey, MJ, Senger, DL, James, MT, Macdonald, JA, Kubes, P, Jenne, CN & Muruve, DA 2018, 'Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury', Journal of Clinical Investigation, vol. 128, no. 7, pp. 2894-2913. https://doi.org/10.1172/JCI96640

Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury. / Lau, Arthur; Chung, Hyunjae; Komada, Takanori; Platnich, Jaye M.; Sandall, Christina F.; Choudhury, Saurav Roy; Chun, Justin; Naumenko, Victor; Surewaard, Bas G.J.; Nelson, Michelle C.; Ulke-Lemée, Annegret; Beck, Paul L.; Benediktsson, Hallgrimur; Jevnikar, Anthony M.; Snelgrove, Sarah L.; Hickey, Michael J.; Senger, Donna L.; James, Matthew T.; Macdonald, Justin A.; Kubes, Paul; Jenne, Craig N.; Muruve, Daniel A.

In: Journal of Clinical Investigation, Vol. 128, No. 7, 02.07.2018, p. 2894-2913.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury

AU - Lau, Arthur

AU - Chung, Hyunjae

AU - Komada, Takanori

AU - Platnich, Jaye M.

AU - Sandall, Christina F.

AU - Choudhury, Saurav Roy

AU - Chun, Justin

AU - Naumenko, Victor

AU - Surewaard, Bas G.J.

AU - Nelson, Michelle C.

AU - Ulke-Lemée, Annegret

AU - Beck, Paul L.

AU - Benediktsson, Hallgrimur

AU - Jevnikar, Anthony M.

AU - Snelgrove, Sarah L.

AU - Hickey, Michael J.

AU - Senger, Donna L.

AU - James, Matthew T.

AU - Macdonald, Justin A.

AU - Kubes, Paul

AU - Jenne, Craig N.

AU - Muruve, Daniel A.

PY - 2018/7/2

Y1 - 2018/7/2

N2 - 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 CX 3 CR1+ 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.

AB - 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 CX 3 CR1+ 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.

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DO - 10.1172/JCI96640

M3 - Article

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