title: Reduced LRP6 expression and increase in the interaction of GSK3β with p53 contribute to podocyte apoptosis in diabetes mellitus and are prevented by green tea.
abstract: In diabetes mellitus (DM), podocyte apoptosis leads to albuminuria and nephropathy progression. Low-density lipoprotein receptor-related protein 6 (LRP6) is WNT pathway receptor that is involved in podocyte death, adhesion and motility. Glycogen synthase kinase 3 (GSK3) interaction with p53 (GSK3-p53) promotes apoptosis in carcinoma cells. It is unknown if GSK3-p53 contributes to podocyte apoptosis in DM. In experimental DM, green tea (GT) reduces albuminuria by an unknown mechanism. In the present study, we assessed the role of the GSK3β-p53 in podocyte apoptosis and the effects of GT on these abnormalities. In diabetic spontaneously hypertensive rats (SHRs), GT prevents podocyte's p-LRP6 expression reduction, increased GSK3β-p53 and high p53 levels. In diabetic SHR rats, GT reduces podocyte apoptosis, foot process effacement and albuminuria. In immortalized mouse podocytes (iMPs), high glucose (HG), silencing RNA (siRNA) or blocking LRP6 (DKK-1) reduced p-LRP6 expression, leading to high GSK3β-p53, p53 expression, apoptosis and increased albumin influx. GSK3β blockade by BIO reduced GSK3β-p53 and podocyte apoptosis. In iMPs under HG, GT reduced apoptosis and the albumin influx by blocking GSK3β-p53 following the rise in p-LRP6 expression. These effects of GT were prevented by LRP6 siRNA or DKK-1. In conclusion, in DM, WNT inhibition, via LRP6, increases GSK3β-p53 and podocyte apoptosis. Maneuvers that inactivate GSK3β-p53, such as GT, may be renoprotective in DM.
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: empeixoto@gmail.com.
authors: E B
authors: EB
authors: Peixoto
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: alexbiochemist@gmail.com.
authors: A
authors: A
authors: Papadimitriou
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: teixeiradatt@gmail.com.
authors: D A T
authors: DA
authors: Teixeira
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: chiara_montemurro@libero.it.
authors: C
authors: C
authors: Montemurro
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: diegoandreazzi@yahoo.com.br.
authors: D A
authors: DA
authors: Duarte
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: kamila@fcm.unicamp.br.
authors: K C
authors: KC
authors: Silva
authors: Department of Histology and Embryology, Biology Institute, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: pjoaz@unicamp.br.
authors: P P
authors: PP
authors: Joazeiro
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: jmlfaria@fcm.unicamp.br.
authors: J M
authors: JM
authors: Lopes de Faria
authors: Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: jblfaria@fcm.unicamp.br.
authors: J B
authors: JB
authors: Lopes de Faria
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000628:therapy; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D050199:Podocytes / Q000166:cytology*; D051381:Rats; D011918:Rats, Inbred SHR; D013662:Tea; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555477:Lrp6 protein, rat; D013662:Tea; D016159:Tumor Suppressor Protein p53; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Diabetic nephropathy; GSK3β (glycogen synthase kinase 3β); Green tea; Podocyte apoptosis; p53