Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats.
BACKGROUND
The antifibrotic substance pirfenidone and the angiotensin II type I receptor antagonist candesartan cilexetil, given alone and in combination, were tested in rats with chronic anti-glomerular basement membrane glomerulonephritis (anti-GBM GN).


METHODS
Male Wistar rats with anti-GBM GN were treated for 8 weeks with candesartan (4 mg/kg body weight/day), pirfenidone (500 mg/kg body weight/day) or a combination of both drugs. One GN group received no treatment and untreated non-GN-rats were used as controls. Blood pressure and urinary protein excretion were measured after 3 and 7 weeks. Kidney histology was complemented by ultrastructural investigation and by quantification of collagen Ialpha mRNA.


RESULTS
The percentage of glomeruli with adsorption droplets in podocytes correlated well with the amount of proteinuria (r = 0.873, P<0.01) and was significantly lowered in rats treated with candesartan (8.3 vs GN 24.6%), pirfenidone (9.8%) and combined treatment (2.6%, P<0.05 vs candesartan alone). A comparable lowering was seen for segmental sclerosis (GN 11%, candesartan 0.7%, P<0.05 vs GN, pirfenidone 1.8%, P = 0.09 vs GN, candesartan/pirfenidone 0.1%, P>0.5 vs candesartan alone). Cortical collagen Ialpha mRNA expression was significantly decreased in all treatment groups. Ultrastructural investigation showed an amelioration of basement membrane alterations and podocyte damage in the treatment groups. Candesartan caused significant blood pressure reduction and the effect was significantly enhanced by combination therapy after 3 weeks. Rats treated with pirfenidone showed blood pressure values similar to control rats.


CONCLUSIONS
Pirfenidone has a beneficial effect on morphological changes in anti-GBM GN comparable with candesartan although with a trend to slightly better results with candesartan treatment. Moreover, our results suggest an additive effect of combination treatment.
Leh
Sabine
S
Renal Research Group, Institute of Internal Medicine, University of Bergen, Bergen, Norway. sabine.leh@helse-bergen.no
Vaagnes
Øyvind
Ø
Margolin
Solomon B
SB
Iversen
Bjarne M
BM
Forslund
Terje
T
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies; D001323:Autoantibodies; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D001707:Biopsy, Needle; D001713:Biphenyl Compounds; D001774:Blood Chemical Analysis; D001795:Blood Pressure Determination; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000473:pathology*; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D008297:Male; D008969:Molecular Sequence Data; D011336:Probability; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012079:Renal Circulation / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013777:Tetrazoles / Q000494:pharmacology*
D000906:Antibodies; D001323:Autoantibodies; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011728:Pyridones; D012333:RNA, Messenger; D013777:Tetrazoles; C051951:antiglomerular basement membrane antibody; C093844:pirfenidone; C081643:candesartan