Heterogeneous Nuclear Ribonucleoprotein F Mediates Insulin Inhibition of Bcl2-Modifying Factor Expression and Tubulopathy in Diabetic Kidney

• Published in: Scientific reports Vol. 9; no. 1; p. 6687
• Main Authors: Ghosh, Anindya, Zhao, Shuiling, Lo, Chao-Sheng, Maachi, Hasna, Chenier, Isabelle, Lateef, Muhammad Abdul, Abdo, Shaaban, Filep, Janos G., Ingelfinger, Julie R., Zhang, Shao-Ling, Chan, John S. D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.04.2019; Nature Publishing Group
• Subjects: 38; 38/1; 38/109; 38/22; 38/44; 38/70; 38/71; 38/77; 38/89; 631/337/572/2102; 631/443/272/1684; 64; 64/110; 64/60; 692/4022/1585/104; 82; 82/29; 82/51; 82/80; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomarkers; Blood pressure; Blood Pressure - genetics; Creatinine; Diabetes; Diabetes mellitus; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Disease Models, Animal; Gene Expression Regulation - drug effects; Genetic Loci; Glucose - metabolism; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; Humanities and Social Sciences; Humans; Immunohistochemistry; Insulin; Insulin - metabolism; Insulin - pharmacology; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Kidneys; Kinases; MAP kinase; Mice; Mice, Transgenic; multidisciplinary; Protein kinase; Regulatory sequences; Science; Science (multidisciplinary); siRNA; Transcription; Transfection; Transgenic mice
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-43218-2

We investigated the molecular mechanism(s) by which insulin prevents Bcl2-modifying factor (Bmf)-induced renal proximal tubular cell (RPTC) apoptosis and loss in diabetic mice. Transgenic mice (Tg) mice specifically overexpressing human BMF in RPTCs and non-Tg littermates were studied at 10 to 20 weeks of age. Non-diabetic littermates, diabetic Akita mice +/− insulin implant, Akita Tg mice specifically overexpressing heterogeneous nuclear ribonucleoprotein F (hnRNP F) in their RPTCs and immortalized rat renal proximal tubular cells (IRPTCs) were also studied. BMF -Tg mice exhibited higher systolic blood pressure, urinary albumin/creatinine ratio, RPTC apoptosis and urinary RPTCs than non-Tg mice. Insulin treatment in Akita mice and Akita mice overexpressing hnRNP F suppressed Bmf expression and RPTC apoptosis. In hyperinsulinemic-euglycemic wild type mice, renal Bmf expression was down-regulated with up-regulation of hnRNP F . In vitro , insulin inhibited high glucose-stimulation of Bmf expression, predominantly via p44/42 mitogen-activated protein kinase (MAPK) signaling. Transfection of p44/42 MAPK or hnRNP F small interfering RNA (siRNA) prevented insulin inhibition of Bmf expression. HnRNP F inhibited Bmf transcription via hnRNP F-responsive element in the Bmf promoter. Our results demonstrate that hnRNP F suppression of Bmf transcription is an important mechanism by which insulin protects RPTCs from apoptosis in diabetes.