Comparison of the renal effects of bisphenol A in mice with and without experimental diabetes. Role of sexual dimorphism.

Bisphenol-A (BPA), a chemical -xenoestrogen- used in the production of the plastic lining of food and beverage containers, is present in the urine of almost the entire population. Recent studies have shown that BPA exposure is associated with podocytopathy, increased urinary albumin excretion (UAE), and hypertension. Since these changes are characteristic of early diabetic nephropathy (DN), we explored the renal effects of BPA and diabetes including the potential role of sexual dimorphism. Male and female mice were included in the following animals' groups: control mice (C), mice treated with 21.2 mg/kg of BPA in the drinking water (BPA), diabetic mice induced by streptozotocin (D), and D mice treated with BPA (D + BPA). Male mice form the D + BPA group died by the tenth week of the study due probably to hydro-electrolytic disturbances. Although BPA treated mice did not show an increase in serum creatinine, as observed in D and D + BPA groups, they displayed similar alteration to those of the D group, including increased in kidney damage biomarkers NGAL and KIM-1, UAE, hypertension, podocytopenia, apoptosis, collapsed glomeruli, as well as TGF-β, CHOP and PCNA upregulation. UAE, collapsed glomeruli, PCNA staining, TGF-β, NGAL and animal survival, significantly impaired in D + BPA animals. Moreover, UAE, collapsed glomeruli and animal survival also displayed a sexual dimorphism pattern. In conclusion, oral administration of BPA is capable of promoting in the kidney alterations that resemble early DN. Further translational studies are needed to clarify the potential role of BPA in renal diseases, particularly in diabetic patients.pre-print3531 K

Peroxisome proliferator activated receptor gamma 2 modulates late pregnancy homeostatic metabolic adaptations.

Pregnancy requires the adaptation of maternal energy metabolism including expansion and functional modifications of adipose tissue. Insulin resistance (IR), predominantly during late gestation, is a physiological metabolic adaptation that serves to support the metabolic demands of fetal growth. The molecular mechanisms underlying these adaptations are not fully understood and may contribute to gestational diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPARγ) controls adipogenesis, glucose and lipid metabolism and insulin sensitivity. The PPARγ2 isoform is mainly expressed in adipocytes and is thus likely to contribute to adipose tissue adaptation during late pregnancy. In the present study, we investigated the contribution of PPARγ2 to the metabolic adaptations occurring during the late phase of pregnancy in the context of IR. Using a model of late pregnancy in PPARγ2 knockout (KO) mice, we found that deletion of PPARγ2 exacerbated IR in association with lower serum adiponectin levels, increased body weight and enhanced lipid accumulation in liver. Lack of PPARγ2 provoked changes in the distribution of fat mass and preferentially prevented the expansion of the perigonadal depot while at the same time exacerbating inflammation. PPARγ2KO pregnant mice presented adipose tissue depot-dependent decreased expression of genes involved in lipid metabolism. Collectively, these data indicate that PPARγ2 is essential to promote healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness: BFU2012-33594 and BFU2013-47384-R to GMG; SAF2015- 64287-R to M. Ricote; and SAF2014-56671-R to MPR; predoctoral fellowship BES-2010- 038107 to YV; and grants S2010/BMD-2423 from the Community of Madrid to MPR and GMG. The authors thank Saverio Cinti for his helpful comments with histological samples, Antonio Vidal-Puig for his help in discussion and Lucia Torres for technical assistance.S

Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

Abstract: When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life

Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

Abstract: When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life

Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARγ expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPARγ in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPARγ is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPARγ have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPARγ in renal metabolism as a likely key factor in the maintenance of systemic homeostasis

The role of PPARγ in endoplasmic reticulum (ER) stress in podocyte injury induced by palmitic acid

Resumen del póster presentado al XXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Valencia del 7 al 10 de septiembre de 2015.-- et al.Changes in lifestyle and dietary habits have raised the overall incidence of obesity. Obese patients often suffer other comorbidities such as hypertension, heart disease, dyslipidaemia, type 2 diabetes and renal disease. Recently, evidences suggest that renal lipid accumulation leads to glomerular damage and more specifi cally, whether this accumulation produces podocyte dysfunction. An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. As a defense mechanism, cells express ER stress inducible chaperons, as glucose-regulated proteins (GRPs).The aim of this study was to analyze the role of PPARγ in the maintenance of the integrity of the podocyte and the involvement of ER stress in podocyte injury induced by palmitic acid (PA) and/or High Glucose (HG). We have used two lines of mouse podocytes (WT and PPARγ knockdown) treated with PA (500μM) and/or HG(25mM) with/without the thiazolidinedione Pioglitazone (Pio) (0.1 μm) for 24h. PA treatment produced oxidative stress and endoplasmic reticulum stress by IRE1 pathway with 10- fold increase in gene expression of GRP78, sXBP1and CHOP. Furthermore rearrangements of the actin cytoskeleton (CD2AP) by PA was observed in the WT podocyte, but these effects were signifi cant greater in podocytes PPARγ knockdown. Pio prevented PA-induced injury in WT podocyte, but this injury did not ameliorated in podocytes PPARγ knockdown. This study suggests a crucial role PPARγ in the protection against ER stress in the podocyte injury induced by Palmitic acid.Fundación de la SEEN, MINECO (BFU2013-47384-R), CAM (S2010/BMD-2423) y Ayudas a la Movilidad 2012 URJC.S2010/BMD-2423/MOIRPeer reviewe

Inmunolocalización en la retina humana de POMT1 y POMT2, dos O-manosil transferasas de proteínas asociadas al síndrome de Walker-Warburg

Resumen del póster presentado al XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Barcelona del 5 al 8 de septiembre de 2011.Las distroglicanopatías son un grupo de distrofias musculares recesivas raras que afectan con mayor o menor gravedad al músculo, ojo y cerebro. Se caracterizan por una hipoglicosilación del α-distroglicano (α-DG), una proteína implicada en el anclaje celular a la lámina basal y el establecimiento de sinapsis en el SNC. La más severa es el síndrome de Walker-Warburg, que conlleva graves defectos cerebrales y oculares y está causado principalmente por mutaciones en el gen POMT1, y con menor frecuencia en POMT2. Estos genes codifican las proteína O-manosil transferasas-1 y -2 responsables de glicosilar el α-DG. Hasta la fecha no se ha estudiado su expresión en la retina de mamíferos adultos. En este trabajo describimos que el gen POMT1 se expresa a nivel de mRNA y proteína en la retina adulta de todos los mamíferos estudiados, desde roedores hasta la especie humana. Hemos detectado asimismo diversas isoformas putativas de POMT1. También hemos investigado el patrón de inmunolocalización de POMT1 y POMT2 en los distintos tipos neuronales y gliales de la retina humana. Hemos determinado que ambas proteínas se colocalizan en las células gliales de Müller. POMT1 y POMT2 también se observan en fotorreceptores (segmentos externos e internos), así como en algunas células bipolares, amacrinas y ganglionares. Dado el amplio patrón de expresión de POMT1 y POMT2, proponemos que estas proteínas podrían desempeñar otras funciones en la retina adulta humana adicionales a su papel descrito en la Oglicosilación del α-DG.Instituto de Salud Carlos III PI09/1623 (J.M.N.) y PI09/0343 (J.C.).Peer Reviewe

Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes.

In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome