Abstract: FR-PO977
Sex-Dependent Modulation of Systolic Blood Pressure and Glucosuria in Tubule-Specific Heterogeneous Nuclear Ribonucleoprotein F Knockout Mice
Session Information
- Pathology and Lab Medicine: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1601 Pathology and Lab Medicine: Basic
Authors
- Lo, Chao-Sheng, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada
- Miyata, Kana N., Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada
- Zhao, Shuiling, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada
- Chenier, Isabelle, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, 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, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada
- Chan, John S.D., Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada
Background
We previously reported that mice with selective tubular deficiency of heterogeneous nuclear ribonucleoprotein F (hnRNP F) exhibit elevated systolic blood pressure (SBP) and glucosuria associated with up-regulation of renal angiotensinogen (Agt) and down-regulation of sodium-glucose co-transporter-2 (Sglt2) (2018 ASN TH-OR073). Here, we compared the impact of sex hormones on glucosuria and expression of Agt and Sglt2 in hnRNP F knockout (KO) mice and control littermates (Ctrls).
Methods
HnRNP F KO mice were generated by crossbreeding Pax8-Cre mice with floxed hnRNP F mice on a C57BL/6 background. Male KO mice and Ctrls were subjected to either sham-operation or bilateral castration at 12 weeks (wks) of age and followed until 20 wks of age. Female KO mice and Ctrls underwent either sham-operation or bilateral ovariectomy at the age of 8 wks and then followed until the age of 24 wks. Testosterone were implanted in female KO and Ctrls mice at the age of 8 wks and followed an extra 4 wks. Body weight (BW), SBP, blood glucose (BG), urinary glucose (UG) were monitored. Western blotting and real-time qPCR were used to quantify Agt and Sglt2 expression in renal proximal tubules (RPTs). Human RPTCs (HK-2) ± KO of HNRNP F by CRISPR/Cas9 method were also studied.
Results
Both male and female KO mice exhibited elevated SBP and glucosuria with up-regulation of Agt and down-regulation of Sglt2 expression in RPTs as compared to Ctrls. However, glucosuria disappeared in male KO mice at 12 wks of age whereas female KO mice had persistent glucosuria. Castration restored glucosuria in male KO mice; no change was seen in ovariectomized female mice. Gonadectomy had no effect on UG in Ctrls. Testosterone treatment prevented glucosuria in female KO mice. In vitro, HK-2 cells with HNRNP F KO displayed up- and down-regulation of AGT and SGLT2 expression, respectively. Finally, testosterone but not estrogen stimulated SGLT2 promoter activity in HK-2 cells but not in HK-2 with HNRNPF KO.
Conclusion
Our results indicate that hnRNP F may play an important role in the development of hypertension and glucosuria in mice in a sex-dependent manner through modulation of renal Agt and Sglt2 expression, respectively.
Funding
- Government Support - Non-U.S.