We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action on a type 2 diabetic (T2D) (db/db) mice. Immortalized rat renal proximal tubular cells (IRPTCs) and human T2D kidneys were also studied. Db/db mice developed hyperglycemia, oxidative stress and nephropathy at age 20 weeks compared to their db/m littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in db/db hnRNP F-transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Forkhead Box O3α (Foxo3α) and catalase expression were significantly decreased in RPTCs from db/db mice and normalized in db/db hnRNP F-Tg mice. In vitro, hnRNP F overexpression stimulated Sirtuin-1 and Foxo3α with down-regulation of acetylated p53 expression and prevented down-regulation of Sirtuin-1 and Foxo3α expression in IRPTCs by high glucose plus palmitate. Transfection of Sirtuin-1 small interfering RNA prevented hnRNP F stimulation of Foxo3α and down-regulation of acetylated p53 expression. HnRNP F stimulated Sirtuin-1 transcription via hnRNP F-responsive element in the Sirtuin-1 promoter. Human T2D kidneys exhibited more RPTC apoptosis and lower expression of HnRNP F, SIRTUIN-1 and FOXO3α than non-diabetic kidneys. Our results demonstrate that hnRNP F protects kidneys against oxidative stress and nephropathy via stimulation of Sirtuin-1 expression and signalling in diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1588/-/DC1.
- Received December 23, 2016.
- Accepted April 7, 2017.
- © 2017 by the American Diabetes Association.