An Exploration of the Mechanisms Underlying Proximal Tubular Vacuolization in Mice with Low Expression of the NADPH‐Cytochrome P450 Reductase

Abstract

Cytochrome P450 reductase (CPR or POR) is an obligatory redox partner for all microsomal P450 enzymes. A large, global decrease in POR expression, in a Cpr‐low mouse model, was previously found to lead to altered sex steroid hormone homeostasis, female infertility, and decreased capacity for xenobiotic metabolism. The aim of this study was to further characterize the Cpr‐low mouse model, in order to identify additional phenotypes that may reveal vulnerability in people with low POR expression. Here we report age‐dependent appearance of marked vacuolization in the proximal tubules of 4‐9 month old male (but not female) Cpr‐low mice. The vacuoles, which were negative for fat (Oil‐red O) and glycogen (PAS) staining, were localized in S1/S2, but not S3, segment of the proximal tubules. Proximal tubule vacuolization was also observed in an extrahepatic Cpr‐low mouse model, in which POR expression was normal in the liver, but low elsewhere. Thus, the renal vacuolization in the Cpr‐low mice was not due to a metabolic dysfunction in the liver. Furthermore, the renal vacuolization was associated with an elevation in serum levels of blood urea nitrogen (BUN), a biomarker for deficits in kidney function. These findings suggest that chronic suppression of POR expression may lead to increased susceptibility to renal injuries or diseases.