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Abstract: SA-PO610

Lipopolysaccharide Induces Filtrate Leakage from Tubular Lumen to Interstitial Space via Proximal Tubular TLR4-Dependent Pathway in Mice

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nakano, Daisuke, Kagawa University, Kagawa, Japan
  • Wiig, Helge, University of Bergen, Bergen, Norway
  • Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Titze, Jens, Duke - National University of Singapore, Singapore, Singapore
  • Nishiyama, Akira, Kagawa University Medical School, Kita-Gun, Japan
Background

We previously reported by using intravital imaging technique that lipopolysaccharide (LPS) slowed proximal tubular flow rate in an early phase of endotoxemia. However, the mechanism by which LPS reduced tubular flow rate was unclear. Hereby, we hypothesized that LPS might disrupt tight junction in proximal tubular cells and induce leakage of filtrate through a Toll-like receptor 4 (TLR4)-dependent mechanism.

Methods

Tubular flow rate was determined by the timing of the appearance and disappearance of intravenously injected dyes in the early segments of proximal tubules in mice under 2-photon laser microscopy observation.

Results

LPS at 5 mg/kg did not change the inflow rate of filtrate into the proximal tubules, which reflect unchanged GFR, and significantly reduced the outflow rate from the proximal tubules at 6h. LPS at 15 mg/kg reduced both inflow and outflow rate. Both dosages of LPS induced oliguria. LPS (5 mg/kg) induced paracellular leakage of FITC-inulin and reduced tight junction mRNA expression (occludin and cldn2). LPS also increased water content, interstitial hydrostatic pressure and Na+/K+ ratio in the kidney, indicating the accumulation of extracellular fluid in the interstitium. These changes were diminished by the conditional knock out of TLR4 in proximal tubules. Furthermore, denuding renal capsule further slowed tubular flow down, suggesting that increasing interstitial pressure might counteract the leakage.

Conclusion

Our results suggest that LPS disrupted tight junction of proximal tubular cells via a TLR4-dependent mechanism, resulting in paracellular leakage of filtrate to interstitium in an early phase of endotoxemia in mice.

Funding

  • Government Support - Non-U.S.