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

• Published in: The Journal of nutritional biochemistry Vol. 26; no. 4; pp. 416 - 430
• Main Authors: Peixoto, E.B., Papadimitriou, A., Teixeira, D.A.T., Montemurro, C., Duarte, D.A., Silva, K.C., Joazeiro, P.P., Lopes de Faria, J.M., Lopes de Faria, J.B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2015
• Subjects: Albuminuria - prevention & control; Animals; Apoptosis; Biopsy; Caspase 3 - genetics; Caspase 3 - metabolism; Diabetes Mellitus, Experimental - prevention & control; Diabetic Nephropathies - pathology; Diabetic Nephropathies - therapy; Diabetic nephropathy; Down-Regulation; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Green tea; GSK3β (glycogen synthase kinase 3β); Humans; In Situ Nick-End Labeling; Kidney - metabolism; Kidney - pathology; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; Male; Mice; Microscopy, Electron, Transmission; p53; Podocyte apoptosis; Podocytes - cytology; Rats; Rats, Inbred SHR; Tea; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Wnt Signaling Pathway; ESRD; CO2; DM; DN; MTT; CTGF; LRP6; p53; IFN-γ; Podocyte apoptosis; TUNEL; ANOVA; FBS; iMPs; STZ; Diabetic nephropathy; SHR; Green tea; Pf-α; TRPC6; VEGF; S.D; BIO; siRNA; GT; AER; FZD; GSK3β; NG; TEM; GSK3β (glycogen synthase kinase 3β); HG
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2014.11.012

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.