Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats

1 Fibrosis leads to chronic impairment of cardiac and renal function and th us reversal of existing fibrosis may improve function and survival. This pr oject has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the m ajor extracellular matrix proteins, collagen and fibronectin, and functiona l changes in the streptozotocin(STZ)-diabetic rat. 2 Streptozotocin (65 mg kg(-1) i.v.)-treated rats given pirfenidone (5-meth yl-1-phenyl-2-[1H]-pyridone; approximately-200 mg kg(-1) day(-1) as 0.2-2g l(-1) drinking water) or spironolactone (50 mg kg(-1) day(-1) s.c.) for 4 w eeks starting 4 weeks after STZ showed no attenuation of the increased bloo d glucose concentrations and increased food and water intakes which charact erize diabetes in this model. 3 STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, rena l and plasma fibronectin concentrations increased in STZ-diabetic rats. Pas sive diastolic stiffness increased in isolated hearts from STZ-diabetic rat s. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased + dP/dt(max) of STZ-diabetic hearts. 4 Left ventricular papillary muscles from STZ-treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or s pironolactone treatment. STZ-treatment transiently decreased GFR and urine flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. 5 Thus, short-term pirfenidone and spironolactone treatment reversed cardia c and renal fibrosis and attenuated the increased diastolic stiffness witho ut normalizing cardiac contractility or renal function in STZ-diabetic rats .