Defective Proximal Tubule Lysosomal Acidification by Bence Jones Proteins

Abstract

Proximal tubule handling of two human Bence Jones proteins (neutral and acidic BJP) was evaluated using protein A-gold labelling. After 30 min of acute light-chain infusion into 6 rats (alone or in combination with dinitrophenyl-aminopropyl-methylamine [DAMP]), kidney biopsies were processed for immunoelectron microscopy. Antibodies directed at monoclonal lambda light chains, mannose-6-phosphate cation-independent receptor (MPR) and DAMP were used.Labelling density (number of pA-gold particles/µm²), expressed as median (25–75 percentiles), differed (p < 0.05) between the two BJP, being 94.5 (32.9–212.5) vs. 19.4 (3.7–45.6) pA-gold/µm² in endocytic vacuoles, and 297.3 (207.1–382.1) vs. 83.2 (16.6–197.0) pA-gold/µm² in non-vacuolar electrondense endosome-lysosome structures. Labelling density for MPR was 47.7 (22.2–84.6) vs. 4.0 (2.7–6.3) pA-gold/µm². The area of MPR-labelled structures was also different, i.e.: 0.2 (0.1–0.4) vs. 0.9 (0.5–1.8) µm². The endosome-lysosome pH distribution range differed significantly: 6.8 (6.4–7.0) vs. 6.3 (5.8–7.0). There was a significant accumulation of neutral BJP in endocytic structures, an acidification deficit of pre-lysosomes/lysosomes and MPR retention, suggestive of defective receptor recycling with this BJP. Interference with the physiological process of lysosomal acidification may be an important mechanism of higher nephrotoxicity in some BJP.

Nephrotoxicity of Bence-Jones proteins: interference in renal epithelial cell acidification

“…Our laboratory has reported the nephrotoxicity of BJP in acute and chronic models (10,11). On the basis of the present results, we conclude that pI modulates cytotoxicity by mechanisms related to internalization and intracellular directioning and catabolism.…”

Role of the monoclonal chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome

“…FS monoclonal LCs could also impair oxidative phosphorylation and mitochondrial energy supply 5 and interfere with the recycling of specific transporters to the apical membrane of the proximal tubular cells by impairing early endosomal and lysosomal acidification. 34,43 In that regard, our present model should be of great help for identifying the cellular targets of reabsorbed monoclonal nephrotoxic light chains and for testing drugs potentially counteracting these effects.…”

Toward Understanding Renal Fanconi Syndrome: Step by Step Advances through Experimental Models

“…Studies of the effect of LC reabsorption on sodium co-transporters expression and trafficking [31,83,87,97], endosomal acidification [55,98], and mitochondrial energy supply [20] are under investigation in CHEB transgenic mice. In this model, which mimics the most frequent form of monoclonal LC-associated FS, congestion of the endolysosomal compartment of PTEC and the resulting decreased receptor recycling alone might explain proximal tubule dysfunction.…”