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

miR-148a and miR-17–5p synergistically regulate milk TAG synthesis via <i>PPARGC1A</i> and <i>PPARA</i> in goat mammary epithelial cells

<p>MicroRNA (miRNA) are a class of ‘18–25’ nt RNA molecules which regulate gene expression and play an important role in several biologic processes including fatty acid metabolism. Here we used S-Poly (T) and high-throughput sequencing to evaluate the expression of miRNA and mRNA during early-lactation and in the non-lactating (“dry”) period in goat mammary gland tissue. Results indicated that miR-148a, miR-17–5p, <i>PPARGC1A</i> and <i>PPARA</i> are highly expressed in the goat mammary gland in early-lactation and non-lactating periods. Utilizing a Luciferase reporter assay and Western Blot, <i>PPARA</i>, an important regulator of fatty acid oxidation, and <i>PGC1a (PPARGC1A)</i>, a major regulator of fat metabolism, were demonstrated to be targets of miR-148a and miR-17–5p in goat mammary epithelial cells (GMECs). It was also revealed that miR-148a expression can regulate <i>PPARA</i>, and miR-17–5p represses <i>PPARGC1A</i> in GMECs. Furthermore, the overexpression of miR-148a and miR-17–5p promoted triacylglycerol (TAG) synthesis while the knockdown of miR-148a and miR-17–5p impaired TAG synthesis in GMEC. These findings underscore the importance of miR-148a and miR-17–5p as key components in the regulation of TAG synthesis. In addition, miR-148a cooperates with miR-17–5p to regulate fatty acid metabolism by repressing <i>PPARGC1A</i> and <i>PPARA</i> in GMECs. Further studies on the functional role of miRNAs in lipid metabolism of ruminant mammary cells seem warranted.</p

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