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. 2001 Jul;133(5):687-94.
doi: 10.1038/sj.bjp.0704131.

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

G Miric  1 , C Dallemagne, Z Endre, S Margolin, S M Taylor, L Brown
Affiliations

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

G Miric et al. Br J Pharmacol. 2001 Jul.

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/dt(max) 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.

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Figures

Figure 1
Figure 1
Body weight (A), daily water intake (B) and food intake (C) for control (open circle), control+pirfenidone (open triangle), control+spironolactone (open square), STZ (filled circle), STZ+pirfenidone (filled triangle) and STZ+spironolactone (filled square) rats.
Figure 2
Figure 2
Daily pirfenidone dose in control+pirfenidone (open triangles) and STZ+pirfenidone (filled triangles) rats.
Figure 3
Figure 3
Collagen distribution in the left ventricle (A), thoracic aorta (B) and kidney (C) of control (C), control+pirfenidone (CP), control+spironolactone (CSp), STZ (S), STZ+pirfenidone (SP) and STZ+spironolactone (SSp) rats; n=6 [* P<0.05 vs C; ** P<0.05 vs S].
Figure 4
Figure 4
Fibronectin concentration in the left ventricle (A), kidney (B) and plasma (C) of control (C), control+pirfenidone (CP), control+spironolactone (CSp), STZ (S), STZ+pirfenidone (SP) and STZ+spironolactone (SSp) rats; n=6 [* P<0.05 vs C; ** P<0.05 vs S].
Figure 5
Figure 5
Cumulative concentration-response curves for noradrenaline and calcium chloride (A) and EMD 57033 (B) in left ventricular papillary muscles from control (C, open circles) (n=8), STZ (S, filled circles) (n=8), STZ+pirfenidone (SP, filled triangles) (n=8) and STZ+spironolactone (SSp, filled squares) (n=8) rats. [*p<0.05 vs C].
Figure 6
Figure 6
Concentration-response curves for noradrenaline in right atria (n=8) from control (C, open circles), STZ (S, filled circles), STZ+pirfenidone (SP, filled triangles) and STZ+spironolactone (SSp, filled squares) rats.
Figure 7
Figure 7
Concentration-response curves for noradrenaline in thoracic aortic rings (n=8) from control (C, open circles), STZ (S, filled circles), STZ+pirfenidone (SP, filled triangles) and STZ+spironolactone (SSp, filled squares) rats.
Figure 8
Figure 8
Glomerular filtration rates (A), urine flow rates (B), renal arterial flow (C) and fractional excretion of sodium (D) (n=6) in isolated perfused kidneys from control (C, open circles), STZ (4 weeks after STZ, S4, filled diamonds; 8 weeks after STZ, S8, filled circles), STZ+pirfenidone (SP, filled triangles) and STZ+spironolactone (SSp, filled squares) rats.
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