Effects of energy intake on type 1 plasminogen activator inhibitor levels in glomeruli of lupus-prone B/W mice

Abstract

Calorie restriction (CR) and/or reduced energy intake ameliorates the progression of autoimmune renal disease in (NZB x NZW)F1 (B/W) female mice and increases life span. Like other forms of glomerulonephritis, the lupus-like kidney disease observed in these animals is frequently accompanied by glomerular deposition of fibrin and increased accumulation of mesangial matrix. Because alterations in plasminogen activator inhibitor type 1 (PAI-1) expression or function may be involved in both fibrin deposition and accumulation of extracellular matrix, we have studied the effects of CR on the expression of PAI-1 in kidneys from female B/W mice fed either ad libitum or on a 40% CR diet. By immunohistochemistry and immunoblotting, we found that the glomerular levels of PAI-1 antigen were highest in older ad lib fed animals with more advanced glomerular disease. Increased levels of PAI-1 protein were paralleled by increased levels of PAI-1 mRNA in total RNA extracted from renal cortex and in diseased glomeruli as detected by in situ hybridization. CR diminished the accumulation of PAI-1 protein and reduced the expression of PAI-1 mRNA. Thus, glomeruli from animals fed ad lib showed much greater deposition of PAI-1 protein, increased expression of PAI-1 mRNA, and more severe histological abnormalities than animals on a CR diet. The differences between CR and ad lib animals were more pronounced in animals studied at 9 to 10 months versus those at 3 to 4 months of age. These observations indicate that the ameliorating effects of CR include diminished PAI-1 gene expression and decreased localization of PAI-1 in glomeruli.