The effect of perindopril on the intra-renal renin angiotensin system and circulating catecholamines in polycystic kidney disease

Hypertension is a common presenting factor in Polycystic Kidney Disease (PKD) patients prior to the onset of renal failure. The renin angiotensin system (RAS) is a key regulator of blood pressure, through both its direct actions and its influence on the sympathetic nervous system (SNS), both of which may contribute to hypertension in these patients. Circulating angiotensin II (Ang II) levels in hypertensive PKD patients are often normal or reduced, however angiotensin converting enzyme (ACE) blockade is an effective anti-hypertensive therapy. Up-regulation of intra-renal RAS has therefore been postulated as a mechanism driving hypertension in PKD. This study examined if chronic ACE inhibition has influences on intra-renal RAS gene expression and plasma catecholamine levels as an indicator or baseline SNS activity in a rat model of PKD, the Lewis Polycystic Kidney (LPK) rat. LPK rats were treated with perindopril (3mg/kg/day p/o) from 4-12 wks of age. Systolic blood pressure was measured weekly via tail cuff plesmography. Animals were euthanased at 12 weeks and kidneys collected for quantitative RT-PCR for RAS genes (angiotensinogen, renin, ACE I & II, and the ATR1A. Blood was collected for assessment of renal function (serum urea and creatinine) and determination of circulating catecholamine levels by HPLC. Chronic perindopril treatment resulted in a significant reduction in blood pressure in treated LPK (164±13 mm Hg) vs. untreated LPK (226±10 mm Hg) P<0.0001. Intra-renal levels of RAS genes were 2 and 2.6 fold greater in LPK treated animals for renin (P<0.009) and AT1RA (P<0.002) respectively, but unchanged for the other RAS genes studied. Plasma levels of noradrenaline (NAd) and adrenaline (A) were significantly less in the LPK treated (NAd=183±66 pg/mL, A=220±105 pg/mL) vs. untreated LPK (NAd=1257±54pg/mL, A=1608±272pg/mL) (P<0.0001 and P<0.0032) respectively. Serum markers of kidney dysfunction were unchanged between groups. The increase in intra-renal mRNA for renin and the AT1RA are consistent with negative feedback and receptor sensitivity responses. The reduction in blood pressure and reduced levels of circulating catecholamines after treatment with perindopril suggest a relationship between Ang II and SNS activity.