Mineralocorticoid receptor antagonism and aldosterone synthesis inhibition do not improve glomerulosclerosis and renal interstitial fibrosis in a model of chronic kidney allograft injury.
Chronic allograft injury (CAI) is a major cause of late graft failure with a multifactorial pathogenesis; however, in different experiments an inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers ameliorated the progression of chronic renal disease. Different concepts supposed that aldosterone is involved in development and/or progression of renal diseases via interaction with a non-epithelial mineralocorticoid receptor (MR), e.g. reducing neointima formation. Our examinations therefore targeted on the effects of the aldosterone synthase inhibitor fadrozole and the MR antagonist spironolactone compared to vehicle in an established rat model of CAI. In our model of CAI, neither the aldosterone biosynthesis inhibitor nor a direct MR blockade had a positive effect on renal CAI in rats. Fadrozole- and spironolactone-treated animals demonstrated a higher proteinuria value, pathologically elevated potassium values, higher tubulointerstitial damage and markedly increased heart weight/body weight as compared to vehicle. Our observations also suggest that inhibition of the MR or the biosynthesis itself had a bad influence on the amount of sclerotic glomeruli and tubulointerstitial damage. The positive effects of inhibition of aldosterone as described in cardiac models could not yet be detected in kidney recipients.
Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, München, Germany. Tobias.Lahmer @ lrz.tu-muenchen.de
Tobias
T
Lahmer
Rob
R
Hermans
Christoph
C
Schmaderer
Jianxing
J
Chang
Konrad
K
Stock
Jens
J
Lutz
Uwe
U
Heemann
Marcus
M
Baumann
D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000473:pathology
D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone