1. In both humans and the rat, stiff conduit arteries are less able to buffer pulsatile changes in blood pressure, provoking CV and renal outcomes 1. Arterial calcification is associated with hypertension and arterial stiffening 2. Arterial calcification and increase in arterials stiffness is also a hallmark of chronic kidney disease (CKD). 3 1. Keith Ng, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959-F966. 2.London GM, Marchais SJ, Guerin AP. Arterial stiffness and function in end- stage renal disease. Adv Chronic Kidney Dis. 2004;11(2):202-209. 3. Temmar M, Liabeuf S, Renard C, et al. Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens. 2010;28(1):163-169. Increased arterial stiffness and aortic calcification are common for hypertension and kidney disease Background 1

2. Study groups: Untreated Lewis polycystic kidney (LPK), LPK treated with perindopril (3 mg/kg/day p/o in the drinking water) from age 6-12 weeks and normotensive Lewis controls. LPK rats develop an early hypertension and marked aortic calcification. Measurements: Arterial stiffness was measured as aortic pulse wave velocity (PWV) Systolic pressures (SBP) Tissue histomorphology from aortic segments Calcium content (by atomic absorption spectroscopy) Wall elastic modulus (EM) and wall stress (WS) Impact of ACE inhibition on arterial structure and function in a model of cystic renal disease Methods 1. Keith Ng, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959-F966.

3. Significant reduced aortic calcification in treated with perindopril LPK rats 1. Keith Ng, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959-F966. P<0.05

4. Perindopril improves elastin density (A,B)… …and reduces pathological collagen deposit (C,D) 1. Keith Ng, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959-F966.

5. Significant reduction in blood pressure and improvement in aortic elasticity indices Treatment with perindopril limits an age-related increase in blood pressure and reduction in aortic elasticity, which naturally occurs in polycystic rats (LPK) between 6 and 12 weeks of age.

6. ACE inhibition with perindopril brought the 12-wk-old LPK curves back to the same level as 12-wk-old normotensive Lewis control animals Treatment with perindopril limits progressive aortic stiffening in polycystic kidney model 1. Keith Ng, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959-F966.

7. Conclusions Compared to normotensive Lewis controls, polycystic kidney (LKP) rats become hypertensive, have marked aortic calcification and remodeling. This is the first study to show that sustained treatment with perindopril can produce a marked inhibition of the progression of hypertension, calcification and associated arterial stiffness in a naturally occurring rodent model of CKD. Further investigation of the renin-angiotensin system and its inhibition may open up improved treatment pathways for complex disease conditions that are associated with the development of arterial calcification and increased arterial stiffness. 1. Keith Ng, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959-F966. ACE inhibition with perindopril improved the structural and functional indices of aortic stiffness