Kidney Week

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

• Hypertension and CVD: Basic Mechanisms
  October 25, 2018 | Location: 6F, San Diego Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• Lo, Chao-Sheng, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Chao-Sheng Lo, PhD



I received my Ph.D. degree from Kaoshung Medical University, Taiwan. I joined Dr. John SD Chan’s lab as a postdoctoral in the University of Montreal, Canada. Currently, I am a research associate in CHUM research center. My interesting is focus on the kidney how to modulate the blood pressure, particularly in some disease model like diabetes. Also, hypertension is now recognized as a key contributory factor in the development and progression of kidney disease in diabetes. Recent clinical trials also support the utility of blood pressure reduction in the prevention of diabetic kidney disease. The control of the blood pressure represents a key component for the prevention and management of diabetic kidney disease. Thus, exploring the underlying mechanism of intrarenal angiotensinogen may have a potential on target of modulating the blood pressure. Dr. Chan’s lab has identified a novel nuclear protein (Heterogeneous Nuclear Ribonucleoprotein F, hnRNPF) which binds on the rat angiotensinogen promoter. I started from renal proximal tubular hnRNPF transgenic mice and cross-breed with diabetic type 1 Akita mice (Diabetes 2012) and type 2 db/db mice (Diabetes 2017). These results show that hnRNP F plays a modulatory role and can ameliorate hypertension, renal hypertrophy and interstitial fibrosis in diabetes. The underlying mechanism is mediated, at least in part, via the suppression of intrarenal Agt gene expression in vivo. Moreover, by employing the Cre/lox system to generate tubular hnRNPF KO mice show elevated SBP and up-regulated angiotensinogen expression in non-diabetic mice. It is convincing that hnRNP F may be a potential target in the treatment of hypertension and kidney injury. In the future, I hope to be able to combine my expertise in experimental therapeutics and diabetic nephropathy, which is often linked to cardiovascular disease, as an independent investigator to explore and cure chronic kidney disease.

• Chenier, Isabelle, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Isabelle Chenier,

• Filep, Janos G., Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada

Janos G. Filep,

• Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States

Julie R. Ingelfinger,

• Zhang, Shao-Ling, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Shao-Ling Zhang,

• Chan, John S.D., CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

John S.D. Chan,

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.