ARB/ACE- I INFLAMMATION PPAR-γ ACTIVITY SPPAR γM POSITIVE NEGATIVE PROTEINURIA ANG II AGES ALDOSTERONE Blockade of RAAS in diabetic kidney disease HYPERGLYCEMIA ROS CYTOKINES TISSUE DISTRUCTION FIBROSIS WEIGHT GAIN, FLUID/Na RETENTION, EDEMA Figure 1 Schematic showing the current understanding of important players and pathways contributing to diabetic nephropathy/diabetic kidney disease. Point of action for telmisartan with dual ARB plus selective PPAR-γ agonist properties is highlighted. Positive indicates action favoring DKD and negative indicates protection against DKD. Sprague Dawley (SD) rats, led to glomerulosclerosis, hypertension, and kidney damage.12 Administration of the mineralocorticoid receptor (MR ) blocker (spironolactone) ameliorated and reversed the harmful effects of aldosterone. A recent study, Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) Trial, showed that the addition of a renin inhibitor to an ARB in diabetic and hypertensive patients decreases proteinuria further when compared with an ARB alone.13 Statins have been proposed to have pleiotropic effects, actions independent of their cholesterol-lowering mechanism. These include decreased ROS generation via inhibition of NADPH oxidase and therefore have a role as renoprotective agent.14 Large randomized controlled trials designed to target DKD populations may be able to provide comprehensive answers as to the usefulness of these drugs. Strong evidence points to the expression of all RAAS components in the kidneys, including the podocytes and Vascular Health and Risk Management 2009:5 tubular cells.15 High glucose stimulates expression of renin and angiotensinogen in mesangial and tubular cells. This stimulation results in an increase in local Ang II concentra- tions which may, in turn, through autocrine and paracrine pathways induce several cytokines and growth factors. Therefore blockade of the overexpressed RAAS will lead to renoprotection. Taking into account the many effects of the RAAS in the pathophysiology of DKD, early treatment with drugs interfering with the tissue effects of RAAS are a necessary prerequisite to prevent development and progres- sion of DKD.16 Lessons from clinical trials on RAAS-blockade Blockade of the RAAS is pivotal in the management of DKD as described above. Strong evidence favors the use of ACE inhibitors and ARBs in patients with type 2 diabetes 131