Heterogeneous Nuclear Ribonucleoprotein F Stimulates Sirtuin-1 Gene Expression and Attenuates Nephropathy Progression in Diabetic Mice.

Abstract

We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (<i>db</i>/<i>db</i>). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The <i>db</i>/<i>db</i> mice developed hyperglycemia, oxidative stress, and nephropathy at age 20 weeks compared with their <i>db</i>/<i>m</i> littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in <i>db</i>/<i>db</i><i>hnRNP F</i>-transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Foxo3α, and catalase expression were significantly decreased in RPTCs from <i>db</i>/<i>db</i> mice and normalized in <i>db</i>/<i>db</i><i>hnRNP F</i>-Tg mice. In vitro, hnRNP F overexpression stimulated Sirtuin-1 and Foxo3α with downregulation of acetylated p53 expression and prevented downregulation of Sirtuin-1 and Foxo3α expression in IRPTCs by high glucose plus palmitate. Transfection of <i>Sirtuin-1</i> small interfering RNA prevented hnRNP F stimulation of Foxo3α and downregulation of acetylated p53 expression. hnRNP F stimulated <i>Sirtuin-1</i> transcription via <i>hnRNP F</i>-responsive element in the <i>Sirtuin-1</i> promoter. Human T2D kidneys exhibited more RPTC apoptosis and lower expression of hnRNP F, SIRTUIN-1, and FOXO3α than nondiabetic kidneys. Our results demonstrate that hnRNP F protects kidneys against oxidative stress and nephropathy via stimulation of <i>Sirtuin-1</i> expression and signaling in diabetes.