Effect of Direct Renin Inhibition on Renal Hemodynamic Function, Arterial Stiffness, and Endothelial Function in Humans With Uncomplicated Type 1 Diabetes

Abstract

OBJECTIVEBlockade of the renin-angiotensin system (RAS) plays an important role in preventing end-organ injury associated with diabetes. The recent development of direct renin inhibitors (DRIs) provides a new approach to block the RAS, but the effects of DRIs on renal and systemic vascular function in uncomplicated type 1 diabetes have not been elucidated.RESEARCH DESIGN AND METHODSRenal hemodynamic function (inulin and paraaminohippurate clearance), augmentation index and pulse wave velocity, endothelial dependent vasodilatation (flow-mediated dilation [FMD]), and endothelial independent vasodilatation (response to sublingual nitroglycerin) were evaluated before and after administration of aliskiren (300 mg daily for 30 days) in 10 adult subjects with uncomplicated type 1 diabetes during clamped euglycemia (4–6 mmol/l) and hyperglycemia (9–11 mmol/l).RESULTSIn response to the DRI, plasma renin activity decreased (from 0.40 to 0.13 ng · ml−1 · h−1, P < 0.05) and plasma renin increased (from 5.2 to 75.0 ng/l, P < 0.05). Peripheral and central blood pressures decreased, and effective renal plasma flow and glomerular filtration rate increased during clamped euglycemia and hyperglycemia (P < 0.05). The carotid augmentation index during clamped euglycemia decreased (from 26 ± 6 to 20 ± 5%, P < 0.05) as did pulse wave velocity during clamped hyperglycemia (from 7.8 ± 0.6 to 6.8 ± 0.5 m/s, P < 0.05). In response to the DRI, FMD increased during both clamped euglycemia (from 1.92 ± 1.13 to 5.55 ± 0.81%) and hyperglycemia (from 1.86 ± 0.98 to 5.63 ± 0.62) as did the vasodilatory response to sublingual nitroglycerin.CONCLUSIONSDRIs exert a renal vasodilatory effect and improve parameters of systemic vascular function, suggesting that blockade of the RAS with this new class of agents has important functional effects in subjects with uncomplicated type 1 diabetes.

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

“…Whether the protective effect observed with lowsodium diet and RAAS inhibition in this post hoc analysis was due to greater haemodynamic effects, enhanced antiinflammatory effects or both, is unknown and requires further study. Nevertheless, as previously reported by our group [17][18][19] and by other investigators [46], RAAS inhibitors still exert prominent haemodynamic effects on the intrarenal RAAS in the presence of relative RAAS suppression induced by a high-salt diet in diabetic patients. Our results extend this previous haemodynamic-focused body of work by suggesting that RAAS inhibition during salt repletion also reduces inflammatory urinary cytokines/chemokines.…”

“…Although it is known that RAAS blockade is more effective under conditions of dietary sodium depletion, RAAS inhibitors are still effective in both diabetic and non-diabetic sodium-replete individuals [17][18][19][20]. These observations suggest persistent intrarenal RAAS activation despite high dietary sodium intake.…”

Aliskiren as a novel therapeutic agent for hypertension and cardio-renal diseases

“…Aliskiren 300 Aliskiren exerted a renal vasodilatory effect, suggesting that blockade of the RAAS may improve uncomplicated type 1 diabetes 10 Cherney et al [79] [81] 2007…”

“…• In patients with uncomplicated type 1 diabetes [79] • In patients with symptomatic heart failure [73] • In patients with type 2 diabetes, hypertension and albuminuria [78] …”

Renal Hyperfiltration Is Associated With Glucose-Dependent Changes in Fractional Excretion of Sodium in Patients With Uncomplicated Type 1 Diabetes

“…Furthermore, given the role of hyperglycemia and subsequent glycosuria leading to increased SGLT2 activity and reduced sodium excretion, it is important to define the effect of euglycemia and hyperglycemia on renal sodium handling. Accordingly, we examined a cohort of young patients with T1D, either with renal hyperfiltration or normofiltration (4,19,20), and compared them with a similar cohort of healthy control (HC) participants under clamped euglycemic conditions. We then repeated studies the next day in a subgroup of the T1D cohort using a hyperglycemic clamp.…”