5 research outputs found
Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes
Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying
mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor
blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the
fatty-acid accumulation and apoptotic responses have not been revealed.
Methods: Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker
Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was
examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes
were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose
exposed cells.
Results: In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis
and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis.
Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes,
high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation
of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and
apoptosis were also significantly ameliorated by eplerenone.
Conclusions: By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and
subsequent remodelling and diastolic dysfunction in obese/type-II diabetic ratsThis work was supported by national grants from Ministerio de Educación y
Ciencia (SAF2009-08367), Comunidad de Madrid (CCG10-UAM/BIO-5289),
FISS (PI10/00072), and a grant from by Pfizer (NY, USA), Spanish Ministry of
Economy and Competitiveness (MINECO) CTQ2011-23562. These grants were
used to provide consumables and animals required. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of
the manuscript. AF received funding from the European Union Seventh
Framework Programme [FP7/2007-2013] under grant agreement nº 26486
Gremlin activates the smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells
Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming
growth factor-(TGF-β). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial
cells we have recently described that Gremlin induces EMT and acts as a downstream TGF-β mediator. Our aim was to investigate
whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2)
with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and
Smad-dependent gene transcription). The blockade of TGF-β, by a neutralizing antibody against active TGF-β, did not modify
Gremlin-induced early Smad activation.These data showthatGremlin directly, by a TGF-β independent process, activates the Smad
pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF-β production and caused a sustained Smad
activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation,
diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF-β neutralization also diminished Gremlininduced
EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular
epithelial cells through activation of Smad pathway and induction of TGF-βThis work was supported by grants from the Instituto
de Salud Carlos III (PI11/01854 and REDINREN ISCIIIRETIC
RD12/0021/0002 and 0001), Sociedad Española de
NefrologÃa, PCI Iberoamerica (A/9571/07), CYTED IBERERC,
FONDECYT Chile 1080083 and 1120480, Comunidad
de Madrid (Fibroteam S2010/BMD-2321, S2010/BMD-
2378), Programa Intensificación Actividad Investigadora
(ISCIII/Agencia LaÃn Entralgo/CM) to A.O. Fundación para
el fomento en Asturias de la investigaciónn cientÃica aplicada
y la tecnologÃa (FICYT)
Estudio del sistema IGE, basófilo PAF (factor agregante de las plaquetas) en las glomerulonefritis experimentales y humanas y en transplantados renales
Tesis doctoral original inédita, leÃda el 20 de julio de 1978 en la Universidad de Autonoma de Madrid, Facultad de Medicin
Fcγ receptor deficiency attenuates diabetic nephropathy
Among patients with diabetes, increased production of immunoglobulins against proteins modified by
diabetes is associated with proteinuria and cardiovascular risk, suggesting that immune mechanisms may
contribute to the development of diabetes complications, such as nephropathy. We investigated the
contribution of IgG Fcg receptors to diabetic renal injury in hyperglycemic, hypercholesterolemic mice.
Weused streptozotocin to induce diabetes in apolipoprotein E–deficientmice and in mice deficient in both
apolipoprotein E and g-chain, the common subunit of activating Fcg receptors. After 15 weeks, the mice
lacking Fcg receptors had significantly less albuminuria and renal hypertrophy, despite similar degrees of
hyperglycemia and hypercholesterolemia, immunoglobulin production, and glomerular immune deposits.
Moreover, diabetic Fcg receptor–deficient mice had less mesangial matrix expansion, inflammatory cell
infiltration, and collagen and a-smooth muscle actin content in their kidneys. Accordingly, expression of
genes involved in leukocyte infiltration, fibrosis, and oxidative stress was significantly reduced in diabetic
kidneys and in mesangial cells cultured from Fcg receptor–deficient mice. In summary, preventing the
activation of Fcg receptors alleviates renal hypertrophy, inflammation, and fibrosis in hypercholesterolemic
mice with diabetes, suggesting that modulating Fcg receptor signaling may be renoprotective in
diabetic nephropathyThis study was supported by grants from Spanish Ministry of
Science (SAF2009/11794), Ministry of Health (PI10/00072, RECAVA
RD06/0014/0035), Lilly Foundation, FRIAT, and Spanish Society of
Nephrolog