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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.

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