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The effects of chronic administration of albumin modified by advanced glycation (AGE) on renal tissue: characterization of the inflammatory, antioxidant and epigenetic profile

Grant number: 14/17251-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2015
Effective date (End): August 26, 2018
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Maria Lucia Cardillo Corrêa Giannella
Grantee:Karina Thieme
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/04831-1 - New players in glycemic control and chronic complications of Diabetes mellitus: preventive and therapeutic perspectives, AP.TEM
Associated scholarship(s):16/04591-1 - Non-coding RNAs in diabetic kidney disease, BE.EP.PD

Abstract

Diabetes mellitus (DM) is the major cause of chronic kidney disease in the world and glomerular dysfunction is the most common etiologic factor for kidney function loss. Hyperglycemia participates in the development of diabetic nephropathy (DN), among other pathways, through the increased production of advanced glycation end products (AGEs). However only a few studies have evaluated the effects of AGEs in the absence of hyperglycemia and this is an important aspect, since exogenous AGEs also exert deleterious effects. AGEs not excreted by the kidneys are distributed in the tissues, remain biologically active and can cause local inflammation, oxidative stress and stimulate other systems, such as the renin-angiotensin system (RAS). Thus, the main hypothesis of this study is that AGEs contribute to DN regardless of hyperglycemia, by changing the expression of pro-fibrotic, pro-inflammatory, and anti-oxidant genes, stimulating the RAS and inducing epigenetic alterations. The second hypothesis is that treatment with the antioxidant N-acetylcysteine (NAC) could prevent the effects of AGEs. The aims of this study are: 1) to evaluate in vivo the effects of chronic treatment with glycated albumin and the possible therapeutic action of NAC on renal function and morphology, induction of oxidative stress, expression of genes involved in this process and epigenetic mechanisms; 2) to evaluate in vitro, in kidney cells (podocytes and mesangial cells), the effects of glycated albumin and the possible therapeutic effects of NAC on the expression of pro and anti-oxidant genes, secretion of cytokines / growth factors, induction of oxidative stress and the involvement of epigenetic mechanisms; 3) to study in vitro, in podocytes, the effect of glycated albumin and the possible therapeutic effects of NAC on the expression of proteins involved in cell adhesion and cytoskeleton arrangement. The results of this study will be important to understand the molecular mechanisms through which AGEs can affect renal physiology and represents an important strategy in the search for future preventive and / or therapeutic approaches to correct the kidney injury, especially on mesangial cells and podocytes. (AU)

Scientific publications (7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GONCALVES, GUILHERME LOPES; COSTA-PESSOA, JULIANA MARTINS; THIEME, KARINA; LINS, BRUNA BEZERRA; OLIVEIRA-SOUZA, MARIA. Intracellular albumin overload elicits endoplasmic reticulum stress and PKC-delta/p38 MAPK pathway activation to induce podocyte apoptosis. SCIENTIFIC REPORTS, v. 8, DEC 20 2018. Web of Science Citations: 3.
CARDOSO, VANESSA GEROLDE; GONCALVES, GUILHERME LOPES; COSTA-PESSOA, JULIANA MARTINS; THIEME, KARINA; LINS, BRUNA BEZERRA; MALAVAZZI CASARE, FERNANDO AUGUSTO; DE PONTE, MARIANA CHARLEAUX; SARAIVA CAMARA, NIELS OLSEN; OLIVEIRA-SOUZA, MARIA. Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-delta/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity. BMC Nephrology, v. 19, JUL 13 2018. Web of Science Citations: 7.
PINTO-JUNIOR, DANILO C.; SILVA, KAROLLINE S.; MICHALANI, MARIA L.; YONAMINE, CAIO Y.; ESTEVES, JOAO V.; FABRE, NELLY T.; THIEME, KARINA; CATANOZI, SERGIO; OKAMOTO, MARISTELA M.; SERAPHIM, PATRICIA M.; CORREA-GIANNELLA, MARIA L.; PASSARELLI, MARISA; MACHADO, UBIRATAN F. Advanced glycation end products-induced insulin resistance involves repression of skeletal muscle GLUT4 expression. SCIENTIFIC REPORTS, v. 8, MAY 25 2018. Web of Science Citations: 4.
DA SILVA, KAROLLINE S.; PINTO, PAULA R.; FABRE, NELLY T.; GOMES, DIEGO J.; THIEME, KARINA; OKUDA, LIGIA S.; IBORRA, RODRIGO T.; FREITAS, VANESSA G.; SHIMIZU, MARIA H. M.; TEODORO, WALCY R.; MARIE, SUELY K. N.; WOODS, TOM; BRIMBLE, MARGARET A.; PICKFORD, RUSSELL; RYE, KERRY-ANNE; OKAMOTO, MARISTELA; CATANOZI, SERGIO; CORREA-GIANNELA, MARIA L.; MACHADO, UBIRATAN F.; PASSARELLI, MARISA. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats. FRONTIERS IN PHYSIOLOGY, v. 8, SEP 22 2017. Web of Science Citations: 5.
FABRE, NELLY T.; THIEME, KARINA; SILVA, KAROLLINE S.; CATANOZI, SERGIO; CAVALEIRO, ANA MERCEDES; PINTO, JR., DANILO A. C.; OKAMOTO, MARISTELA M.; MORAIS, MYCHEL RAONY P. T.; FALQUETTO, BARBARA; ZORN, TELMA M.; MACHADO, UBIRATAN E.; PASSARELLI, MARISA; CORREA-GIANNELLA, MARIA LUCIA. Hormetic modulation of hepatic insulin sensitivity by advanced glycation end products. Molecular and Cellular Endocrinology, v. 447, n. C, p. 116-124, MAY 15 2017. Web of Science Citations: 3.
DE PONTE, MARIANA CHARLEAUX; MALAVAZZI CASARE, FERNANDO AUGUSTO; COSTA-PESSOA, JULIANA MARTINS; CARDOSO, VANESSA GEROLDE; MALNIC, GERHARD; MELLO-AIRES, MARGARIDA; VOLPINI, RILDO APARECIDO; THIEME, KARINA; OLIVEIRA-SOUZA, MARIA. The Role of beta-Adrenergic Overstimulation in the Early Stages of Renal Injury. Kidney & Blood Pressure Research, v. 42, n. 6, p. 1277-1289, 2017. Web of Science Citations: 1.
THIEME, KARINA; DA SILVA, KAROLLINE S.; FABRE, NELLY T.; CATANOZI, SERGIO; MONTEIRO, MARIA BEATRIZ; SANTOS-BEZERRA, DANIELE PEREIRA; COSTA-PESSOA, JULIANA MARTINS; OLIVEIRA-SOUZA, MARIA; MACHADO, UBIRATAN F.; PASSARELLI, MARISA; CORREA-GIANNELLA, MARIA LUCIA. N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 40, n. 3-4, p. 608-620, 2016. Web of Science Citations: 3.

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