TY - JOUR
T1 - Identification of kidney injury–released circulating osteopontin as causal agent of respiratory failure
AU - Khamissi, Fatima Zohra
AU - Ning, Liang
AU - Kefaloyianni, Eirini
AU - Dun, Hao
AU - Arthanarisami, Akshayakeerthi
AU - Keller, Amy
AU - Atkinson, Jeffrey J.
AU - Li, Wenjun
AU - Wong, Brian
AU - Dietmann, Sabine
AU - Lavine, Kory
AU - Kreisel, Daniel
AU - Herrlich, Andreas
N1 - Funding Information:
A.H. and this work were supported by NIH RO1s DK121200, DK108947, and VA Merit Award BX005322, and E.K. was supported by the American Heart Association Career Development Award 20CDA35320006 and the American Society of Nephrology Career Development Award (KidneyCure Carl W. Gottschalk Research Scholar Grant).
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.
PY - 2022/2
Y1 - 2022/2
N2 - Tissue injury can drive secondary organ injury; however, mechanisms and mediators are not well understood. To identify interorgan cross-talk mediators, we used acute kidney injury (AKI)–induced acute lung injury (ALI) as a clinically important example. Using kidney and lung single-cell RNA sequencing after AKI in mice followed by ligand-receptor pairing analysis across organs, kidney ligands to lung receptors, we identify kidney-released circulating osteopontin (OPN) as a novel AKI-ALI mediator. OPN release from kidney tubule cells triggered lung endothelial leakage, inflammation, and respiratory failure. Pharmacological or genetic OPN inhibition prevented AKI-ALI. Transplantation of ischemic wt kidneys caused AKI-ALI, but not of ischemic OPN–global knockout kidneys, identifying kidney-released OPN as necessary interorgan signal to cause AKI-ALI. We show that OPN serum levels are elevated in patients with AKI and correlate with kidney injury. Our results demonstrate feasibility of using ligand-receptor analysis across organs to identify interorgan cross-talk mediators and may have important therapeutic implications in human AKI-ALI and multiorgan failure.
AB - Tissue injury can drive secondary organ injury; however, mechanisms and mediators are not well understood. To identify interorgan cross-talk mediators, we used acute kidney injury (AKI)–induced acute lung injury (ALI) as a clinically important example. Using kidney and lung single-cell RNA sequencing after AKI in mice followed by ligand-receptor pairing analysis across organs, kidney ligands to lung receptors, we identify kidney-released circulating osteopontin (OPN) as a novel AKI-ALI mediator. OPN release from kidney tubule cells triggered lung endothelial leakage, inflammation, and respiratory failure. Pharmacological or genetic OPN inhibition prevented AKI-ALI. Transplantation of ischemic wt kidneys caused AKI-ALI, but not of ischemic OPN–global knockout kidneys, identifying kidney-released OPN as necessary interorgan signal to cause AKI-ALI. We show that OPN serum levels are elevated in patients with AKI and correlate with kidney injury. Our results demonstrate feasibility of using ligand-receptor analysis across organs to identify interorgan cross-talk mediators and may have important therapeutic implications in human AKI-ALI and multiorgan failure.
UR - http://www.scopus.com/inward/record.url?scp=85125317161&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abm5900
DO - 10.1126/sciadv.abm5900
M3 - Article
C2 - 35213222
AN - SCOPUS:85125317161
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 8
M1 - eabm5900
ER -