Role of transforming growth factor-beta1 in the progression of chronic allograft nephropathy.
Chronic allograft nephropathy is the principal cause of late graft loss after the first year of renal transplantation. Transforming growth factor-beta1 (TGF-beta1) is a key fibrogenetic cytokine involved in the fibrosis of a number of chronic diseases of the kidney and other organs, and recently evidence has shown that TGF-beta1 is involved in the pathogenesis of chronic renal allograft dysfunction. Production of TGF-beta1 in these circumstances may be modulated by the intrarenal renin-angiotensin system (angiotensin II induces TGF-beta1 production and secretion by the mesangial cells) and by a direct effect of cyclosporin A, which stimulates the synthesis and expression of TGF-beta1. In a prospective study of 14 renal transplant patients exhibiting chronic graft nephropathy, we demonstrated that treatment with losartan significantly decreased plasma levels of TGF-beta1 by >50%. There was a significant correlation (P=0.04) between the increase in circulating angiotensin II after 2 weeks and the decrease in plasma TGF-beta(1) at the end of the study period, suggesting that the degree of angiotensin II receptor blockade plays a decisive role in the synthesis of TGF-beta1. A significant decrease in circulating endothelin-1 (ET-1) levels also occurred during treatment with losartan, together with a decrease in proteinuria. In a randomized 2x2 crossover study, the effects of losartan and amlodipine on renal haemodynamics and on profibrogenetic cytokines were analysed. Whereas amlodipine increased the glomerular filtration rate (GFR) through an increase in the FF and P(G), losartan slightly decreased the GFR, but with a significant decrease in FF and P(G). With respect to the profibrogenetic cytokines, losartan decreased the plasma levels of TGF-beta1 and ET-1, while amlodipine did not significantly change TGF-beta1 and slightly increased ET-1.
Campistol
J M
JM
Renal Transplant Unit, Hospital Clinic, Institut d'Investigació Biomediques Agusti Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Iñigo
P
P
Larios
S
S
Bescos
M
M
Oppenheimer
F
F
D000804:Angiotensin II / Q000097:blood; D000959:Antihypertensive Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D018450:Disease Progression; D019332:Endothelin-1 / Q000097:blood; D006801:Humans; D016030:Kidney Transplantation / Q000473:pathology* / Q000502:physiology*; D019808:Losartan / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000097:blood / Q000502:physiology*; D014184:Transplantation, Homologous
D000959:Antihypertensive Agents; D015415:Biomarkers; D019332:Endothelin-1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019808:Losartan