Renal tubular uptake and transport of albumin. Implications for renal physiology and drug targeting

Background
Albumin is a carrier of hormones, vitamins, toxins, and drugs, and is used to modulate drug pharmacokinetics and targeting. The kidney proximal tubule is a major site for uptake and metabolism of albumin and essential for understanding the mechanisms of albuminuria in kidney disease. We have established the essential role of the cubilin/megalin receptor complex for tubular uptake and lysosomal degradation of filtered albumin. Recent evidence suggests that filtered albumin may be transport intact across the kidney proximal tubule. If this process is physiological important this will significantly change present-day understanding of renal albumin handling. Conjugation to albumin is extensively used for modifying drug metabolism and further characterization of these processes may identify new ways to modulate renal handling and toxicity of albumin conjugate drugs.

The project
This project investigates the importance of renal tubular transport of intact albumin for normal albumin turnover and explores the possibility of specific targeting different renal albumin transport pathways. Using mouse receptor knockout models we will determine the physiological importance of such pathway and its role in normal albumin metabolism. Furthermore, we will explore differences in renal handling of albumin variants with different affinities for the receptors as a way to modulate targeting and metabolism of albumin conjugated drugs. The overall aim is to develop strategies 1) by which renal albumin catabolism may be modified to attenuate progression in albumuric kidney diseases and 2) to modulate renal drug handling.

Specific aims:

  • To determine the importance of renal tubular transport of intact albumin for the normal metabolism of albumin.
  • To explore the role of the neonatal Fc-receptor for the renal uptake and tubular recovery of filtered albumin.
  • To test the hypothesis that modifying albumin (albumin variants) may target this for different.

Perspectives:
Successful characterization of the physiological importance of FcRn dependent albumin transport will significantly increase current understanding of renal protein metabolism and its implications in normal physiology. It will provide the basis for further experimental studies of renal tubular albumin transport or catabolism as modulators of albumin accumulation in progressive kidney disease and as target for treatment. The ability to target different albumin transport pathways using albumin variants should enable modulation of renal drug handling by conjugation and modification of half-life, effect, and toxicity. Cubilin and megalin are expressed in several absorptive epithelia and this approach may be equally relevant in tissues other than the kidney expressing cubilin/megalin and/or FcRn.

The project is supported by the Danish Council for Independent Research (Grant-ID: DFF – 4004-00222).

Participants in the project:

  • Henrik Birn, professor MSO, (PI, Grant licensee)
  • Post doc/PhD-student N.N.
  • Rikke Nielsen, associate professor
  • Erik Ilsø Christensen, professor
  • Kathrin Weyer, post doc
  • Helle Salling Gittins, technician