The role of lysosomes in hyaline droplet nephropathy induced by a variety of pharmacological agents in the male rat

Abstract

The male rat is prone to hyaline droplet formation in renal proximal tubular cells. Several unrelated pharmaceutical agents exacerbate the formation and accumulation of these droplets. Where the loading of the proximal tubular cells is marked it gives rise to increased cell turnover and a hyaline droplet nephropathy develops. Cytochemical procedures, have confirmed that this accumulation of hyaline droplets represents an increase in the size and number of secondary lysosomes involved in protein uptake and metabolism. This predisposition of the male rat to develop hyaline droplet nephropathy relates to (1) the large amounts of the low-molecular-weight protein alpha 2U globulin in the glomerular filtrate, (2) the resistance of the globulin to proteolysis, and (3) the low protease activity in the proximal tubule lysosomes. The current data would suggest that the pharmacological agents, which cause the nephropathy, exert their effect by reducing the proteolytic breakdown of alpha 2U globulin in the proximal tubule lysosomes. This results in the overloading of a system which is already operating near maximal load. Female rats, and all other species excrete only small amounts of alpha 2U globulin or similar proteins, which are more easily hydrolyzed. Thus it is argued that the type of hyaline droplet nephropathy induced by these pharmacological agents is unique to the male rat and of little relevance to man.

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

“…5-II). As denoted earlier, α2u-globulin is a prominent male rat urinary protein which is nearly exclusively degraded in renal lysosomes (Read 1991). As expected, α2u-globulin accumulations were highly prominent in the cytosol of both control and propiverine-treated male rats (Fig.…”

“…Of note, the analogous mouse urinary protein (MUP) does not bind the α2u-binding compounds nor does it accumulate in the renal proximal tubules of mice (Dietrich and Rasonyi 1995), reminiscent of the situation described for the species-specific propiverine-induced rDAAO accumulation. Similar to rDAAO but more accentuated, α2u-globulin leads to renal protein overload already under normal physiological conditions (Read 1991;Shimoyama et al 2014). However, while reduced enzymatic metabolism of α2u-globulin exacerbates only the accumulation in the lysosomes of the renal proximal tubules, exacerbated propiverine-induced rDAAO accumulation occurs in the cytosol and the nuclei of the renal proximal tubules (Cuervo et al 1999;Dietrich et al 2008).…”

Lamotrigine kidney distribution in male rats following a single intraperitoneal dose

“…In fact, taking into account the basic and lipophilic properties of the molecule of LTG together with the carrier specificity of this protein for lipophilic ligands, it can be suggested that LTG, when bounded to the α ‐2U‐globulin, makes it more resistant to hydrolysis and/or, when accumulated in the lysosomes, has a direct inhibitory effect on lysosomal function. This reduction of the proteolytic breakdown of α ‐2U‐globulin occurs in the proximal tubule lysosomes, which are located in the cortical region of the kidney [6,7].…”

“…In the male rat, besides a good distribution of the antiepileptic drug through all organs and tissues, an accumulation of LTG in the kidneys was observed [5]. This accumulation was attributed to alterations in the renal handling of α ‐2U‐globulin in this species and gender [6,7]. It was suggested that this effect could partly explain the maintenance of LTG serum concentrations over a long period of time [8].…”

Chaperone-Mediated Autophagy in the Kidney: The Road More Traveled

“…Hyaline droplet nephropathy (also called α 2 -microglobulin nephropathy), which occurs after exposure to a variety of aliphatic, alicyclic, or aromatic compounds (ie, hydrocarbons), is associated with acute kidney injury and the possibility of renal tubular carcinogenesis during recovery. 94 The hyaline droplets that form inside tubular cells are actually lysosomes with a high concentration of α 2 -microglobulin. Exposure to hydrocarbons induces increased lysosomal LAMP-2A, presumably by inducing oxidative stress.…”