Renal inflammation induces salt sensitivity in male db/db mice through dysregulation of ENaC

Background Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. Methods Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. Results Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. Conclusions The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.Fil: Veiras, Luciana Cecilia. Cedars Sinai Medical Center; Estados UnidosFil: Shen, Justin Z. Y.. Cedars Sinai Medical Center; Estados UnidosFil: Bernstein, Ellen A.. Cedars Sinai Medical Center; Estados UnidosFil: Regis, Giovanna C.. Cedars Sinai Medical Center; Estados UnidosFil: Cao, DuoYao. Cedars Sinai Medical Center; Estados UnidosFil: Okwan Duodu, Derick. Cedars Sinai Medical Center; Estados UnidosFil: Khan, Zakir. Cedars Sinai Medical Center; Estados UnidosFil: Gibb, David R.. Cedars Sinai Medical Center; Estados UnidosFil: Dominici, Fernando Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados UnidosFil: Giani, Jorge Fernando. Cedars Sinai Medical Center; Estados Unido

One-Year Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement for Stenotic Bicuspid versus Tricuspid Aortic Valves: A Meta-Analysis and Meta-Regression

Objective. To assess 1-year mortality after transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic stenosis (AS). Background. Clinical trials have proven the beneficial effect of TAVR on mortality in patients with tricuspid AS. Individuals with bicuspid AS were excluded from these trials. Methods. A meta-analysis using literature search from the Cochrane, PubMed, ClinicalTrials, SCOPUS, and EMBASE databases was conducted to determine the effect of TAVR on 1-year mortality in patients with bicuspid AS. Short-term outcomes that could potentially impact one-year mortality were analyzed. Results. After evaluating 380 potential articles, 5 observational studies were selected. A total of 3890 patients treated with TAVR were included: 721 had bicuspid and 3,169 had tricuspid AS. No statistically significant difference between the baseline characteristics of the two groups of patients was seen outside of mean aortic gradient. Our primary endpoint of one-year all-cause mortality revealed 85 deaths in 719 patients (11.82%) with bicuspid AS compared to 467 deaths in 3100 patients (15.06%) with tricuspid AS, with no difference between both groups [relative risk (RR) 1.03; 95% CI 0.70-1.51]. Patients with bicuspid AS were associated with a decrease in device success (RR 0.62; 95% CI 0.45-0.84) and an increase in moderate-to-severe prosthetic valve regurgitation (RR 1.55; 95% CI 1.07-2.22) after TAVR compared to patients with tricuspid AS. The effect of meta-regression coefficients on one-year all-cause mortality was not statistically significant for any patient baseline characteristics. Conclusion. When comparing TAVR procedure in tricuspid AS versus bicuspid AS, there was no difference noted in one-year all-cause mortality

Angiotensin-converting enzyme is required for normal myelopoiesis

Inhibition of angiotensin-converting enzyme (ACE) induces anemia in humans and mice, but it is unclear whether ACE is involved in other aspects of hematopoiesis. Here, we systemically evaluated ACE-knockout (KO) mice and found myelopoietic abnormalities characterized by increased bone marrow myeloblasts and myelocytes, as well as extramedullary myelopoiesis. Peritoneal macrophages from ACE-KO mice were deficient in the production of effector molecules, such as tumor necrosis factor-α, interleukin-12p40, and CD86 when stimulated with lipopolysaccharide and interferon-γ. ACE-KO mice were more susceptible to Staphylococcus aureus infection. Further studies using total or fractionated bone marrows revealed that ACE regulates myeloid proliferation, differentiation, and functional maturation via angiotensin II and substance P and through the angiotensin II receptor type 1 and substance P neurokinin 1 receptors. Angiotensin II was correlated with CCAAT-enhancer-binding protein-α up-regulation during myelopoiesis. Angiotensin II supplementation of ACE-KO mice rescued macrophage functional maturation. These results demonstrate a previous unrecognized significant role for ACE in myelopoiesis and imply new perspectives for manipulating myeloid cell expansion and maturation.—Lin, C., Datta, V., Okwan-Duodu, D., Chen, X., Fuchs, S., Alsabeh, R., Billet, S., Bernstein, K. E., Shen, X. Z. Angiotensin-converting enzyme is required for normal myelopoiesis

Table_1_Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis.docx

The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which contributes to disease progression. We previously reported that mice with increased macrophage-specific angiotensin-converting enzyme, termed ACE10/10 mice, resist atherosclerosis in an adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced model. This is due to increased lipid metabolism by macrophages which contributes to plaque resolution. However, the importance of ACE in peripheral blood monocytes, which are the primary precursors of lesional-infiltrating macrophages, is still unknown in atherosclerosis. Here, we show that the ACE-mediated metabolic phenotype is already triggered in peripheral blood circulating monocytes and that this functional modification is directly transferred to differentiated macrophages in ACE10/10 mice. We found that Ly-6Clo monocytes were increased in atherosclerotic ACE10/10 mice. The monocytes isolated from atherosclerotic ACE10/10 mice showed enhanced lipid metabolism, elevated mitochondrial activity, and increased adenosine triphosphate (ATP) levels which implies that ACE overexpression is already altered in atherosclerosis. Furthermore, we observed increased oxygen consumption (VO2), respiratory exchange ratio (RER), and spontaneous physical activity in ACE10/10 mice compared to WT mice in atherosclerotic conditions, indicating enhanced systemic energy consumption. Thus, ACE overexpression in myeloid lineage cells modifies the metabolic function of peripheral blood circulating monocytes which differentiate to macrophages and protect against atherosclerotic lesion progression due to better lipid metabolism.</p