EFFECTS OF ENERGY-INTAKE ON TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR LEVELS IN GLOMERULI OF LUPUS-PRONE B W MICE/

Calorie restriction (CR) and/or reduced energy intake ameliorates the progression of autoimmune renal disease in (NAB x NZW)F-1 (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 accumula tion of mesangial matrix. Because alterations in plasminogen activator inhibitor type 1 (PAI-1) expression or function may be involved in bo th 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 immunohi stochemistry and immunoblotting, we found that the glomerular levels o f PAI-1 antigen were highest in older ad lib fed animals with more adv anced glomerular disease. Increased levels of PAI-1 protein were paral leled by increased levels of PAI-1 mRNA in total RNA extracted from re nal cortex and in diseased glomeruli as detected by in situ hybridizat ion. CR diminished the accumulation of PAI-1 protein and reduced the e xpression of PAI-1 mRNA. Thus, glomeruli from animals fed ad lib showe d much greater deposition of PAI-1 mRNA, and more severe histological abnormalities than animals on a CR diet. The differences between CR an d ad lib animals were more pronounced in animals studied at 9 to 10 mo nths versus those at 3 to 4 months of age. These observations indicate that the ameliorating effects of CR include diminished PAI-1 gene exp ression adn decreased localization of PAI-1 in glomeruli.