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Background and Purpose Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. Experimental Approach To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT(1) antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. Key Results MAP before treatment was 153 +/- 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. Conclusion and Implications Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.

Background and Objective: In an experiment designed to explore the mechanisms of fludrocortisone‐induced high blood pressure, we serendipitously observed aortic aneurysms in mice infused with fludrocortisone. The purpose of this study was to investigate whether fludrocor-tisone induces aortic pathologies in both normocholesterolemic and hypercholesterolemic mice. Methods and Results: Male adult C57BL/6J mice were infused with either vehicle (85% polyethylene glycol 400 (PEG‐400) and 15% dimethyl sulfoxide (DMSO); n = 5) or fludrocortisone (12 mg/kg/day dissolved in 85% PEG‐400 and 15% DMSO; n = 15) for 28 days. Fludrocortisone‐infused mice had higher systolic blood pressure, compared to mice infused with vehicle. Fludrocortisone induced aortic pathologies in 4 of 15 mice with 3 having pathologies in the ascending and aortic arch regions and 1 having pathology in both the ascending and descending thoracic aorta. No pathologies were noted in abdominal aortas. Subsequently, we infused either vehicle (n = 5/group) or fludrocortisone (n = 15/group) into male ApoE ‐/‐ mice fed a normal laboratory diet or LDL receptor ‐/‐ mice fed either normal or Western diet. Fludrocortisone increased systolic blood pressure, irrespective of mouse strain or diet. In ApoE ‐/‐ mice infused with fludrocortisone, 2 of 15 mice had ascending aortic pathologies, but no mice had abdominal aortic pathologies. In LDL receptor ‐/‐ mice fed normal diet, 5 had ascending/arch pathologies and 1 had pathologies in the ascending, arch, and su-prarenal aortic regions. In LDL receptor ‐/‐ mice fed Western diet, 2 died of aortic rupture in either the descending thoracic or abdominal region, and 2 of the 13 survived mice had ascending/arch aortic pathologies. Aortic pathologies included hemorrhage, wall thickening or thinning, or dila-tion. Only ascending aortic diameter in LDLR ‐/‐ mice fed Western diet reached statistical signifi-cance, compared to their vehicle. Conclusion: Fludrocortisone induces aort

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

OBJECTIVE: Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) exerts beneficial effects on blood pressure and kidney function, but its effects in diabetes are still unknown. DESIGN AND METHOD: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic with streptozotocin for 18 weeks and treated with vehicle, AGT siRNA, the angiotensin receptor blocker valsartan, the ACE inhibitor captopril, valsartan + siRNA, or valsartan + captopril for the final 3 weeks. Arterial pressure was measured via radiotelemetry. RESULTS: Baseline mean arterial pressure (MAP) was 164 ± 1 mm Hg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a further rise in MAP or a change in glomerular filtration rate. All treatments lowered MAP (by ~50 mm Hg) and cardiac hypertrophy identically. Treatment with siRNA resulted in the largest reduction in AGT, while in combination with valsartan AGT virtually disappeared. Only the dual treatment groups and captopril lowered circulating angiotensin II and aldosterone. No treatment affected renal AGT mRNA expression, confirming the liver-specificity of the siRNA. Yet, siRNA with or without valsartan, and valsartan + captopril, but not valsartan alone, or captopril alone, reduced renal angiotensin I and II. All treatments lowered albuminuria and proteinuria, while only siRNA with or without valsartan improved glomerulosclerosis and podocyte dysfunction. Multiple linear regression confirmed both mean arterial pressure and renal angiotensin II as independent determinants of albuminuria. CONCLUSIONS: In conclusion, AGT siRNA exerts renoprotection in diabetic TGR(mREN2)27 rats, and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human diabetic kidney disease.

ABSTRACT: In recent years, perivascular adipose tissue (PVAT) research has gained special attention in an effort to understand its involvement in vascular function. PVAT is recognized as an important endocrine organ that secretes procontractile and anticontractile factors, including components of the renin-angiotensin-aldosterone system, particularly angiotensinogen (AGT). This review critically addresses the occurrence of AGT in PVAT, its release into the blood stream, and its contribution to the generation and effects of angiotensins (notably angiotensin-(1-7) and angiotensin II) in the vascular wall. It describes that the introduction of transgenic animals, expressing AGT at 0, 1, or more specific location(s), combined with the careful measurement of angiotensins, has revealed that the assumption that PVAT independently generates angiotensins from locally synthesized AGT is incorrect. Indeed, selective deletion of AGT from adipocytes did not lower circulating AGT, neither under a control diet nor under a high-fat diet, and only liver-specific AGT deletion resulted in the disappearance of AGT from blood plasma and adipose tissue. An entirely novel scenario therefore develops, supporting local angiotensin generation in PVAT that depends on the uptake of both AGT and renin from blood, in addition to the possibility that circulating angiotensins exert vascular effects. The review ends with a summary of where we stand now and recommendations for future research.