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

Abstract

1 Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing ®brosis may improve function and survival. This project has determined whether pirfenidone, a new anti®brotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and ®bronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. 2 Streptozotocin (65 mg kg 71 i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately 200 mg kg 71 day 71 as 0.2 ± 2g 1 71 drinking water) or spironolactone (50 mg kg 71 day 71 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. 3 STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma ®bronectin concentrations increased in STZ-diabetic rats. Passive diastolic sti ness increased in isolated hearts from STZ-diabetic rats. 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 spironolactone treatment. STZ-treatment transiently decreased GFR and urine¯ow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. 5 Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal ®brosis and attenuated the increased diastolic sti ness without normalizing cardiac contractility or renal function in STZ-diabetic rats.

Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes

“…In agreement with previous reports on diabetic cardiomyopathy in STZ-induced diabetes [16,17], sham-operated diabetic rats in our study had larger LVEDD and higher relative heart weight than non-diabetic controls. However, sustained myocyte apoptosis in diabetic rats was observed only after they had been subjected to MI.…”

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

“…in rats increases blood glucose concentration. After 4 or 8 weeks of streptozotocin administration, animals showed collagen deposition in the kidneys, elevated renal plasma fibronectin concentrations (58) and elevated plasma levels of TGFβ, up to four times the normal levels (14). This model can be considered as a renal fibrosis model because sometimes, after the onset of diabetes, renal fibrosis may occur (58).…”

Immune Activation in the Pathogenesis of Treated Chronic HIV Disease: A Workshop Summary

“…Although not currently FDA approved, pirfenidone is licensed in Japan for the treatment of idiopathic pulmonary fibrosis, and animal models have indicated that pirfenidone can reverse fibrosis in the lungs, kidneys, and other organs. 60 In a pilot study of SIV-infected rhesus macaques, Dr. Schacker and his collaborators determined that pirfenidone had a protective effect on CD4 T cell populations in lymph nodes. A second pilot study looked at the effect of pirfenidone in combination with antiretroviral therapy.…”