Influence of the expression of inflammatory markers on kidney after fetal programming in an experimental model of renal failure

Objective. To evaluate the expression of inflammatory markers in experimental renal failure after fetal programming. Methods. The offspring aged two and fivemonths were divided into four groups: CC (control dams, control offspring)DC (diabetic dams, control offspring)CFA (control dams, folic acid offspring, 250 mg/Kg)and DFA (diabetic dams, folic acid offspring). Gene expression of inflammatory markersMCP-1, IL-1, NOS3, TGF-beta, TNF-alpha, and VEGF was evaluated by RT-PCR. Results. MCP-1 was increased in the CFA and DFA groups at two and fivemonths of age, as well as in DC5 when compared to CC5. There was a higher expression of IL-1 in the CFA2, DFA2, and DC2 groups. There was a decrease in NOS3 and an increase in TNF-alpha in DFA5 in relation to CFA5. The gene expression of TGF-beta increased in cases that had received folic acid at two and five months, and VEGF decreased in the CFA5 and DFA5 groups. DC5 showed increased VEGF expression in comparison with CC5. Conclusions. Gestational diabetes mellitus and folic acid both change the expression of inflammatory markers, thus demonstrating that the exposure to harmful agents in adulthood has a more severe impact in cases which underwent fetal reprogramming.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)Fundacao de Ensino e Pesquisa de Uberaba (FUNEPU)Discipline of General Pathology, Institute of Biological and Natural Sciences, Federal University of Triângulo Mineiro, Uberaba, MG, BrazilDepartment of Health Sciences, Lavras Federal University, Lavras, MG, BrazilDiscipline of Physiology, Institute of Biological and Natural Sciences, Federal University of Triângulo Mineiro, Uberaba, MG, BrazilNephrology Division, Federal University of São Paulo (UNIFESP), São Paulo, SP, BrazilDepartment of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, SP, BrazilDepartment of General Pathology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, GO, BrazilNephrology Division, Federal University of São Paulo (UNIFESP), São Paulo, SP, BrazilWeb of Scienc

Selective human inhibitors of ATR and ATM render Leishmania major promastigotes sensitive to oxidative damage.

All cellular processes, including those involved in normal cell metabolism to those responsible for cell proliferation or death, are finely controlled by cell signaling pathways, whose core proteins constitute the family of phosphatidylinositol 3-kinase-related kinases (PIKKs). Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3 related (ATR) are two important PIKK proteins that act in response to DNA damage, phosphorylating a large number of proteins to exert control over genomic integrity. The genus Leishmania belongs to a group of early divergent eukaryotes in evolution and has a highly plastic genome, probably owing to the existence of signaling pathways designed to maintain genomic integrity. The objective of this study was to evaluate the use of specific human inhibitors of ATR and ATM in Leishmania major. Bioinformatic analyses revealed the existence of the putative PIKK genes ATR and ATM, in addition to mTOR and DNA-PKcs in Leishmania spp. Moreover, it was possible to suggest that the inhibitors VE-821 and KU-55933 have binding affinity for the catalytic sites of putative L. major ATR and ATM, respectively. Promastigotes of L. major exposed to these inhibitors show slight growth impairment and minor changes in cell cycle and morphology. It is noteworthy that treatment of promastigotes with inhibitors VE-821 and KU-55933 enhanced the oxidative damage caused by hydrogen peroxide. These inhibitors could significantly reduce the number of surviving L. major cells following H2O2 exposure whilst also decreasing their evaluated IC50 to H2O2 to less than half of that observed for non-treated cells. These results suggest that the use of specific inhibitors of ATR and ATM in Leishmania interferes in the signaling pathways of this parasite, which can impair its tolerance to DNA damage and affect its genome integrity. ATR and ATM could constitute novel targets for drug development and/or repositioning for treatment of leishmaniases

Morphological and functional aspects of acute kidney injury after fetal programing in the offspring of diabetic rats

Objective: To evaluate the effects of folic acid (FA)-induced renal failure in young offspring of diabetic mothers.Methods: the offspring of streptozotocin-induced diabetic dams were divided into four groups: CC (controls receiving vehicle); DC (diabetics receiving vehicle); CA (controls receiving FA solution, 250 mg/kg) and DA (diabetics receiving FA solution, 250 mg/kg). Renal function tests and morphometry results were analyzed.Results: An increase in creatinine and urea levels was observed in CA and DA groups at two and five months. FA administration caused a significant reduction in the number of glomeruli in the offspring of diabetic dams. the diabetes group treated with FA had fewer glomeruli compared to controls at two and five months. FA caused an increase in the area of the urinary space both in controls and offspring of diabetic dams at two and five months. the number of glomeruli and area of the urinary space at two months were negatively correlated.Conclusions: Fetal programing promotes remarkable changes in kidney morphology and function in offspring. We suggest that the morphological changes in the kidneys are more pronounced when fetal programing is associated with newly acquired diseases, e.g. renal failure induced by FA.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Fundacao de Ensino e Pesquisa de Uberaba (FUNEPU)Univ Fed Triangulo Mineiro, Inst Ciencias Biol & Nat, Disciplina Patol Geral, BR-38025180 Uberaba, MG, BrazilUniv Fed Triangulo Mineiro, Discipline Physiol, Biol & Nat Sci Inst, BR-38025180 Uberaba, MG, BrazilUniv Fed Triangulo Mineiro, Discipline Biochem, Biol & Nat Sci Inst, BR-38025180 Uberaba, MG, BrazilFed Univ São Paulo UNIFESP, Div Nephrol, São Paulo, BrazilUniv São Paulo, Inst Biomed Sci 4, Dept Immunol, BR-09500900 São Paulo, BrazilFed Univ São Paulo UNIFESP, Div Nephrol, São Paulo, BrazilWeb of Scienc