Lrpap1 (RAP) Inhibits Proximal Tubule Clathrin Mediated and Clathrin Independent Endocytosis, Ameliorating Renal Aminoglycoside Nephrotoxicity.

Abstract

Proximal tubules are exposed to many exogenous and endogenous nephrotoxins that pass through the glomerular filter. This includes many small molecules such as aminoglycoside and myeloma light chains. These filtered molecules are rapidly endocytosed by the proximal tubules and lead to nephrotoxicity. To investigate whether inhibition of proximal tubule uptake of filtered toxins can reduce toxicity we evaluated the ability of Lrpap1 or RAP to prevent proximal tubule endocytosis. Munich Wistar Frömter rats were used since both glomerular filtration and proximal tubule uptake can be quantified. The injury model chosen was the well-established gentamicin induced toxicity which leads to significant reductions in GFR and serum creatinine increases. Chronic kidney disease was induced with a right uninephrectomy and left 40 minute pedicle clamp. Rats had eight weeks to recover and to stabilize GFR and proteinuria. Multiphoton microscopy was used to evaluate endocytosis in vivo and serum creatinine and 24 hour creatinine clearances were used to evaluate kidney functional changes. Studies showed preadministration of RAP significantly inhibited both albumin and dextran endocytosis in outer cortical proximal tubules. Importantly, this inhibition was found to be rapidly reversible with time. RAP was also found to be an excellent inhibitor of proximal tubule gentamicin endocytosis. Lastly, gentamicin administration for 6 days resulted in significant elevation of serum creatinine in vehicle treated rats but not those receiving daily infusion of RAP prior to gentamicin. This study provides a model for the potential use of RAP to prevent, in a reversible manner, proximal tubule endocytosis of potential nephrotoxins thus protecting the kidney from damage.