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

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Abstract
Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing fibrosis may improve function and survival. This project has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and fibronectin, and functional changes in the streptozotocin(STZ)‐diabetic rat. Streptozotocin (65 mg kg−1 i.v.)‐treated rats given pirfenidone (5‐methyl‐1‐phenyl‐2‐[1H]‐pyridone; approximately 200 mg kg−1 day−1 as 0.2–2g 1−1 drinking water) or spironolactone (50 mg kg−1 day−1 s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. STZ‐treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma fibronectin concentrations increased in STZ‐diabetic rats. Passive diastolic stiffness increased in isolated hearts from STZ‐diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased +dP/dtmax of STZ‐diabetic hearts. 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 spironolactone treatment. STZ‐treatment transiently decreased GFR and urine flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. Thus, short‐term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ‐diabetic rats. British Journal of Pharmacology (2001) 133, 687–694; doi:10.1038/sj.bjp.0704131