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Abstract: SA-PO613

Mechanism of Difference in Plasma and Urinary Clearance Glomerular Filtration Rate (GFR) Determinations

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Sandoval, Ruben M., Indiana University School of Medicine , Indianapolis, Indiana, United States
  • Campos-bilderback, Silvia B., Indiana University, Indianapolis, Indiana, United States
  • Wagner, Mark C., Indiana University Medical Center, Indianapolis, Indiana, United States
  • Myslinski, Jered, Indiana University School of Medicine , Indianapolis, Indiana, United States
  • Molitoris, Bruce A., Indiana University School of Medicine , Indianapolis, Indiana, United States
Background

It is well established, but not understood, that plasma clearance GFRs exceed urinary clearance GFRs for the same filtered marker, often by 5-10%. Therefore, the present studies were undertaken to determine the role of proximal tubule endocytosis in reducing urinary excretion of filtration markers.

Methods

To visualize and quantify the effect of PTC uptake on reducing urinary GFR determinations freely filterable fluorescently labeled dextrans, inulin and small molecular weight proteins were investigated. All had a glomerular sieving coefficient of 1.0, and given by bolus intravenous administration. Ratiometric analysis of 2-photon images and urinary quantification of neutral (TRITC) and negatively charged (FITC) markers was used to quantify PTC uptake and the effect of charge on PTC uptake.

Results

Intravital 2-photon imaging revealed PTC endocytic uptake of freely filtered GFR markers was rapid, dose and time dependent. pH mediated quenching of FITC fluorescence resulted in a pseudo-reduction in apparent PTC uptake of FITC labeled markers. Neutrally charged fluorescent markers were internalized by PTC S2 > S1. Negatively charged FITC dextrans and inulins were preferentially taken up versus a neutral TRITC inulin, particularly in S1 PTC. Two-photon imaging demonstrated that a negative charge increased PTC uptake, as the injected ratio of FITC /TRITC inulin was increased from 0.504 to 0.729 +/- 0.056 for a 45% increase in negatively charge inulin uptake. On the other hand, the urine FITC/TIRTC ratio decreased 38.7% +/-0.1%, consistent with increased PTC endocytosis of negatively charged inulin.

Conclusion

PTC reabsorbed filtration markers, including inulin, in a dose and time dependent fashion via endocytosis. PTC uptake explains in part the reduction in urinary compared to plasma GFR clearance. Finally, a negative charge on these molecules increases uptake by PTC, especially in the S1 segment.

Funding

  • Other NIH Support