Bichu et al be due to its intrinsic peroxisome proliferator-activated receptor–gamma (PPAR-γ) agonist properties. The incidence of DKD continues to increase in the US and globally. Understanding the mechanisms underlying the development of DKD is essential for establishing novel thera- peutic strategies for the prevention or arrest of progressive disease. Herein, we will review some of these mechanisms as they relate to the AMADEO trial ﬁndings. Pathophysiology and markers of diabetic kidney disease Evidence suggests that up to 44% of patients with diabetes mellitus develop DKD.3 Development of DKD is associated with progressive functional and structural changes in the basic kidney unit, ie, the nephron and glomerulus,4 affected via hemodynamic and metabolic pathways. Hemodynamic and metabolic factors contribute equally towards the devel- opment of DKD, it is now clear that these processes are interlinked. Earlier stages of DKD include a hyperﬁltration mechanism that occurs due to decreased resistance of both afferent and efferent arteriole. Afferent arteriole has greater decrease in resistance than its efferent counterpart. There is defective autoregulation of tone due to complex interaction of mediators including prostanoids, nitric oxide, reactive oxygen species (ROS), lipids, vascular endothelial growth factor (VEGF), transforming growth factor-beta 1 (TGF-β1), high glucose and the RAAS, speciﬁcally angiotensin II (Ang II). These hemodynamic changes and the defect in autoregulation allow an increased ﬁltration of albumin at the level of the glomerulus. It has been shown that proteinuria can occur as a result of molecular and structural abnormali- ties in the podocyte slit diaphragm within the glomerular epithelial cell.6,7 Ang II has been reported to be a primary mediator of loss of the slit-pore diaphragm. In addition to promoting glomerular nephrin depletion, Ang II also appears to have other actions that promote the development of proteinuria, including trophic effects on the kidney and increasing glomerular membrane pore size. This in turn promote structural changes like mesangial cell proliferation, thickening of basement membrane that further potentiate injury to podocytes.6 At the molecular level, hyperglycemia and proteins altered by high blood glucose such as Amadori products and advanced glycation end products (AGEs) are key players in the development of DKD. Evidence suggests that an increase in reactive oxygen species (ROS) forma- tion induced by high glucose-mediated activation of the mitochondrial electron-transport chain is an early event in the development of diabetic complications. A variety 130 of tissue growth factors and cytokines are then induced through complex signal transduction pathways involving protein kinase C (PKC), mitogen-activated protein kinases (MAPK), and the transcription factor NF-κB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines. Particularly, tissue growth factors are important in the development of renal hypertrophy and accumulation of extracellular matrix components. Activation of the renin-angiotensin-aldosterone system (RAAS) by hemodynamic changes, high glucose, mechanical stress, and proteinuria with an increase in local formation of Ang II contribute many of the pathophysiological changes associated with DKD (Figure 1). In fact, it has been shown that Ang II is involved in almost every pathophysiological process implicated in the development of DKD (hemody- namic changes, hypertrophy, extracellular matrix accumu- lation, growth factor/cytokine induction, ROS formation, podocyte damage, proteinuria, interstitial inﬂammation, adverse effects on the balance between the ﬁbrinolytic and thrombotic mechanisms).8 Therefore, interruption of the RAAS via inhibition of Ang II is an essential part of every therapeutic regimen in managing the patient with DKD. Role of drugs blocking RAAS RAAS inhibition is the mainstay of therapy in preventing the progression of DKD. In addition to normalization of systemic and glomerular hypertension, it is now clear that inhibition of the RAAS at various levels by the Ang II antagonists (ACE inhibitors and ARBs) have several renoprotective effects, including anti-inﬂammatory and anti-ﬁbrotic mechanisms.9 Addition of diuretics has been strongly recommended by KDOQI guidelines to achieve target blood pressures of 130 mmHg in cases of recalcitrant hypertension in DKD patients.10 The role for aldosterone antagonist (spironolactone), renin antagonist (aliskiren) and statins in prevention of metabolic derangements consequent to RAAS overactivity in DKD is emerging. In whole animal models, experiments to tease out the non-hemodynamic renoprotective effects of the RAAS antagonists included transgenic rats with a human AT1 receptor (AT1R) gene which overexpressed AT1R.11 These rats developed signiﬁcant albu- minuria, podocyte effacement, progressive ﬁbrosis, leading to focal segmental glomerulosclerosis (FSGS), which were independent of blood pressure and reversed by the blockade of Ang II. Aldosterone has been shown to cause kidney oxidative stress, inﬂammation, ﬁbrosis, and sclerosis. Shibata et al demonstrated that aldosterone infusions and high-salt diet, when administered to uninephrectomized normotensive Vascular Health and Risk Management 2009:5