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Abstract: TH-OR073

Tubular Deficiency of Heterogeneous Nuclear Ribonucleprotein F Enhances Development of Hypertension and Kidney Injury via Elevated Renal Angiotensinogen and Attenuated SGLT2 Expression in Mice

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Lo, Chao-Sheng, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
  • Chenier, Isabelle, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
  • Filep, Janos G., Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
  • Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States
  • Zhang, Shao-Ling, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
  • Chan, John S.D., CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
Background

We reported previously that overexpression of the transcription factor, heterogeneous nuclear ribonucleoprotein F (hnRNP F) in renal proximal tubular cells attenuates systolic blood pressure (SBP), kidney injury and renal angiotensinogen (Agt) gene expression in mice with both type 1 and type 2 diabetes (Diabetes 2012, 2017). Here, we investigated whether deletion of hnRNP F in renal tubules would elevate SBP and aggravate kidney injury through increasing renal Agt gene expression.

Methods

Tubule-specific hnRNP F knockout (KO) mice were generated by crossbreeding Pax8-Cre mice with floxed hnRNP F mice on a C57BL/6 background. Both male and female Pax8-hnRNP F KO mice and control littermates were studied. Body weight (BW), SBP, blood glucose (BG), urinary glucose (UG) and albumin/creatinine ratio (ACR) were monitored up to 24 weeks of age. Kidneys were processed for histology. Western blotting and real-time qPCR were used to quantify hnRNP F, Agt, sodium-glucose co-transporter-2 (Sglt2) protein and mRNA expression in renal proximal tubules (RPTs), respectively.

Results

Both male and female Pax8-hnRNP F KO mice developed hypertension and elevated ACR as compared with control littermates with no detectable differences in BW and BG. Intriquingly, both male and female Pax8-hnRNP F KO mice developed glucosuria at 8 weeks of age. However, glucosuria disappeared in male Pax8-hnRNP F KO at the age of 12 weeks, whereas glucosuria was persistent in females. HnRNP F protein and mRNA expression are barely detectable in RPTs of Pax8-hnRNP F KO mice. In contrast, Agt expression was elevated, and Sglt2 expression was attenuated in RPTs of both male and female Pax8-hnRNP F KO mice as compared to controls at 8 and 24 weeks.

Conclusion

Our data demonstrate that hnRNP F plays an important role in the development of hypertension and kidney injury through modulation of renal Agt expression. Pax8-hnRNP F KO mice may provide a novel experimental model to study the development of glycosuria in non-diabetic mice.

Funding

  • Government Support - Non-U.S.