Circulating Soluble ACE2 Plays an Independent Role to Protect against Vascular Damage in Diabetic Mice.

Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated.

Recent advances in the pharmacotherapeutic management of diabetic kidney disease.

INTRODUCTION: Diabetic kidney disease (DKD) remains a major cause of morbidity and mortality in diabetes and is a key cause of end-stage kidney disease (ESKD) worldwide. Major clinical advances have been confirmed in large trials demonstrating renoprotection, adding to the benefits of existing intensive glucose and blood pressure control therapies. Furthermore, there are exciting new treatments predominantly at an experimental and early clinical phase which appear promising. AREAS COVERED: The authors review DKD in the context of existing and emerging therapies affording cardiorenal benefits including SGLT2 inhibitors and GLP-1 receptor agonists. They explore novel therapies demonstrating potential including a newly developed mineralocorticoid receptor antagonist and endothelin receptor blockade, while evaluating the utility of DPP4 inhibitors in current clinical practice. They also consider the recent evidence of emerging therapies targeting metabolic pathways with enzyme inhibitors, anti-fibrotic agents, and agents modulating transcription factors. EXPERT OPINION: Significant improvements have been made in the management of DKD with SGLT2i and GLP-1 agonists providing impressive renoprotection, with novel progress in renin-angiotensin-aldosterone system (RAAS) blockade with finerenone. There is also great potential for several new experimental therapies. These advances provide us with optimism that the outlook of this devastating condition will continue to improve.

Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target?

OBJECTIVE: We evaluated the influence of the renin-angiotensin system (RAS) on intestinal inflammation and fibrosis. DESIGN: Cultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1-7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies. RESULTS: Human colonic myofibroblast proliferation was reduced by Ang (1-7) in a dose-dependent manner (p<0.05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p<0.001). Colonic myofibroblast collagen secretion was reduced by Ang (1-7) (p<0.05) and captopril (p<0.001), and was increased by Ang II (p<0.001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson's trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=-0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation. CONCLUSIONS: The RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.

Pathophysiological Links Between Diabetes and Blood Pressure.

Hypertension is highly prevalent among people with diabetes, and the presence of diabetes among those with hypertension portends an increase in cardiovascular risk. In this review we aim to explore the pathophysiological links between diabetes and hypertension. Renal sodium handling differs in diabetes because there is an upregulation of sodium transporters in the kidneys. The renin-angiotensin-aldosterone system may be upregulated in diabetes, leading to hypertension through a direct effect mediated by angiotensin II, as well as indirectly through upregulation of sympathetic activity. Renin-angiotensin-aldosterone system blockade is a mainstay therapy for hypertension, and evidence suggests that it might also reduce the incidence of diabetes. People with diabetes frequently have autonomic dysfunction, which could contribute to hypertension through increased sympathetic tone and through stimulation of renin production in the juxtaglomerular apparatus. Furthermore, people with diabetes also frequently show an abnormality in their circadian blood pressure pattern. Another important link between hypertension and diabetes is the development as well as progression of diabetic kidney disease, the pathophysiology of which is mediated through several pathways including endothelial dysfunction and advanced glycation end products. Finally, obesity and the metabolic syndrome, through their effects on various hormones and inflammation, might also contribute to the pathogenesis of hypertension and diabetes.

Isolated renal intravascular lymphoma: a case report and review of the literature.

Intravascular large B-cell lymphoma (IVLBCL) is a very rare subtype of extranodal large B-cell lymphoma. It may involve various organ systems such as skin, liver, lung or kidney. Isolated kidney involvement of IVLBCL is also very rare. Herein we report a very rare case of isolated renal IVLBCL presented with fever of unknown origin, acute kidney injury and nephrotic syndrome. Diagnosis was suspected with isolated high renal (18)F fluorodeoxyglucose uptake in positron emission tomography and confirmed with renal biopsy. Complete remission was obtained with combined chemotherapy including rituximab. We reviewed the English literature in terms of IVLBCL with renal involvement and we could only find 16 such cases. Accordingly, fever, AKI and nephritic syndrome are the most common presenting symptoms in renal intravascular lymphoma.