Bichu et al highest volume of distribution in its class), and high afﬁnity for angiotensin receptor. PPAR-γ agonist effect of telmisartan Telmisartan is the only ARB which acts as a partial agonist of PPAR-γ. PPAR-γ is a ligand activated transcription factor that regulates cell growth, inﬂammation, lipid metabolism and insulin sensitivity. It has been successfully shown that PPAR-γ agonists limit high glucose-induced inﬂammation in proximal tubular cells (PTC).40 PPAR-γ agonists also exert anti-ﬁbrotic effects in human proximal tubular cells under high glucose conditions by attenuating the increase in AP-1, TGF-β1 and downstream production of the extracellular matrix protein, ﬁbronectin. PPAR-γ agonists can improve insulin sensitivity, reduce triglyceride levels and decrease the risk of atherosclerosis. A study examined the ability of different ARBs to activate PPAR-γ in a cell-based transient transfection assay (Figure 2). This assay was designed to eliminate interfer- ence from endogenous nuclear receptors. In the results shown here, each ARB was used at a concentration of 10 mmol/L. Telmisartan was the only ARB to show strong (27-fold) activation, although irbesartan also showed a slight activation (2- to 3-fold). By comparison, full PPAR-γ agonists show ∼140-fold activation in this assay. Importantly, Telmisartan Irbesartan 3 Candesartan Valsartan Olmesartan Eprosartan 1 1 1 Losartan 2.5 27 0 6 12 18 24 PPAR-gamma agonists activity 30 Figure 2 Inherent PPAR-γ agonist activity of various ARBs. Importantly, full PPAR-γ agonists, ie, thiazolidinediones typically have agonist activity in the 150 to 200 range. Drawn from data of.36 136 telmisartan was also the only ARB that activated PPAR-γ when tested at lower concentrations that can be achieved physiologically (1–5 mmol/L). Telmisartan therefore acts as a partial agonist of PPAR-γ.36 There have been reports of sodium and ﬂuid retention associated with full PPAR-γ agonist activity. Evidence suggests that PPAR-γ is highly expressed in the medullary collecting ducts with lower expression levels in glomeruli, proximal tubules and microvasculature and is a major site for increased ﬂuid reabsorption in response to PPAR-γ agonist activity.41,42 In these collecting ducts, PPAR-γ activation increases sodium re-absorption through epithelial sodium channel (ENaC) dependent and independent mechanisms (Na+-K+-ATPase system). Guan et al showed that showed that mice treated with thiazolidinediones (TZDs, full PPAR-γ agonists), experience early weight gain from increased total body water.41 Weight gain was blocked by the collecting duct-speciﬁc diuretic amiloride and was also prevented by deletion of PPAR-γ from the collecting duct, using PPAR-γ (ﬂox/ﬂox) mice. Moreover, treating cultured medullary collecting ducts with TZD increased amiloride- sensitive sodium absorption and mRNA expression of ENaC-γ isoform through a PPAR-γ dependent pathway. Furthermore, in the blood vessels of adipose tissues, PPAR-γ ligands activate protein kinase C (PKC), vascular endothelial growth factor (VEGF), and nitric oxide (NO), which together lead to increased endothelial permeability. Thus increased renal sodium retention at the level of the collecting duct in conjunction with increased vascular permeability may cause edema development and account for the side effects of drugs with full PPAR-γ agonist activity. The above-mentioned adverse effects have caused high attrition rates which led to the need for the discovery and characterization of alternative PPAR modulators that would retain the beneﬁcial properties of these drugs while avoiding the cardiovascular side effects. These are called the Selective Modulators of PPAR-γ activity (SPPARγM).43,46 PPAR-γ receptor is a multivalent receptor whose ligand binding domain can accommodate different ligands (full agonist, partial agonist, or SPPARγM) and is capable of inducing distinct receptor combinations leading to selective gene expression. Each ligand–receptor complex assumes a some- what different three-dimensional conformation, leading to unique and differential interactions with co-factors, histones, and other transcription factors. Consequently, each PPAR-γ ligand-receptor complex leads to a differential, but overlap- ping, pattern of gene expression and ultimately differential biological responses.43,46 Telmisartan has been shown to be a Vascular Health and Risk Management 2009:5