TY - JOUR
T1 - Lipopolysaccharide induces filtrate leakage from renal tubular lumina into the interstitial space via a proximal tubular Toll-like receptor 4–dependent pathway and limits sensitivity to fluid therapy in mice
AU - Nakano, Daisuke
AU - Kitada, Kento
AU - Wan, Ningning
AU - Zhang, Yahua
AU - Wiig, Helge
AU - Wararat, Kittikulsuth
AU - Yanagita, Motoko
AU - Lee, Syann
AU - Jia, Lin
AU - Titze, Jens M.
AU - Nishiyama, Akira
N1 - Publisher Copyright:
© 2019 International Society of Nephrology
PY - 2020/5
Y1 - 2020/5
N2 - Sustained oliguria during fluid resuscitation represents a perplexing problem in patients undergoing therapy for septic acute kidney injury. Here, we tested whether lipopolysaccharide induces filtrate leakage from the proximal tubular lumen into the interstitium, thus disturbing the recovery of urine output during therapy, such as fluid resuscitation, aiming to restore the glomerular filtration rate. Intravital imaging of the tubular flow rate in the proximal tubules in mice showed that lipopolysaccharide did not change the inflow rate of proximal tubule filtrate, reflecting an unchanged glomerular filtration rate, but significantly reduced the outflow rate, resulting in oliguria. Lipopolysaccharide disrupted tight junctions in proximal tubules and induced both paracellular leakage of filtered molecules and interstitial accumulation of extracellular fluid. These changes were diminished by conditional knockout of Toll-like receptor 4 in the proximal tubules. Importantly, these conditional knockout mice showed increased sensitivity to fluid resuscitation and attenuated acute kidney injury. Thus, lipopolysaccharide induced paracellular leakage of filtrate into the interstitium via a Toll-like receptor 4-dependent mechanism in the proximal tubules of endotoxemic mice. Hence, this leakage might diminish the efficacy of fluid resuscitation aiming to maintain renal hemodynamics and glomerular filtration rate.
AB - Sustained oliguria during fluid resuscitation represents a perplexing problem in patients undergoing therapy for septic acute kidney injury. Here, we tested whether lipopolysaccharide induces filtrate leakage from the proximal tubular lumen into the interstitium, thus disturbing the recovery of urine output during therapy, such as fluid resuscitation, aiming to restore the glomerular filtration rate. Intravital imaging of the tubular flow rate in the proximal tubules in mice showed that lipopolysaccharide did not change the inflow rate of proximal tubule filtrate, reflecting an unchanged glomerular filtration rate, but significantly reduced the outflow rate, resulting in oliguria. Lipopolysaccharide disrupted tight junctions in proximal tubules and induced both paracellular leakage of filtered molecules and interstitial accumulation of extracellular fluid. These changes were diminished by conditional knockout of Toll-like receptor 4 in the proximal tubules. Importantly, these conditional knockout mice showed increased sensitivity to fluid resuscitation and attenuated acute kidney injury. Thus, lipopolysaccharide induced paracellular leakage of filtrate into the interstitium via a Toll-like receptor 4-dependent mechanism in the proximal tubules of endotoxemic mice. Hence, this leakage might diminish the efficacy of fluid resuscitation aiming to maintain renal hemodynamics and glomerular filtration rate.
KW - fluid resuscitation
KW - oliguria
KW - proximal tubules
UR - http://www.scopus.com/inward/record.url?scp=85079902513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079902513&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2019.11.024
DO - 10.1016/j.kint.2019.11.024
M3 - Article
C2 - 32107020
AN - SCOPUS:85079902513
SN - 0085-2538
VL - 97
SP - 904
EP - 912
JO - Kidney international
JF - Kidney international
IS - 5
ER -