Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells

Telmisartan, an angiotensin II receptor type 1 blocker (ARB), was recently reported to promote lipolysis in mice by acting as a peroxisome proliferator-activated receptor (PPAR)-delta activator, although in clinical studies, it has also been recognized to activate PPAR-c as a major cause of its pleiotropic actions. The aim of this study was to investigate whether telmisartan activates endogenous PPAR-delta and thereby exerts anti-fibrotic effects in human mesangial cells (HMC). Immunohistochemical analysis of human renal biopsy specimens revealed that PPAR-delta protein was detected in the HMC of glomeruli with moderately proliferative changes. In the HMC, both GW0742, an authentic PPAR-delta agonist, and telmisartan enhanced PPAR response element (PPRE)-luciferase activity dose dependently, and these increases were blunted by GSK0660, a specific PPAR-delta antagonist, but not by GW9662, a PPAR-c antagonist. Telmisartan also upregulated the expression of PPAR-delta target genes related to fatty acid oxidation; that is, heart type-fatty acid-binding protein and uncoupling protein-2. These effects were inhibited by both PPAR-delta antagonism and PPAR-delta gene silencing. Transforming growth factor-beta 1 (TGF-beta 1) increased the expression of plasminogen activator inhibitor-1 (PAI-1), TGF-beta 1 and collagen IV. The PAI-1 expression was mediated, at least in part by the phosphorylation of extracellular signal-regulated kinases (ERKs). Telmisartan suppressed TGF-beta 1-stimulated PAI-1 and collagen IV expression and ERK phosphorylation, and these effects were weakened by PPAR-delta antagonism, whereas eprosartan, a non-PPAR activating ARB, did not affect TGF-beta 1-stimulated PAI-1 expression. These results indicate that in HMC telmisartan activates endogenous PPAR-delta and may prevent TGF-beta 1-induced fibrotic changes by reducing ERK phosphorylation in a PPAR-delta-dependent manner, and thus, might be useful for treating hypertensive patients with renal and metabolic disorders.