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Kidney Week

Abstract: FR-PO185

Loss of Heterogeneous Nuclear Ribonucleoprotein F in Renal Tubules Attenuates Hyperfiltration and Kidney Injury in Diabetic Mice via Downregulation of SGLT2 Expression

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Miyata, Kana N., CRCHUM,University of Montreal, Montreal, Quebec, Canada
  • Lo, Chao-Sheng, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
  • Zhao, Shuiling, CRCHUM, Montreal, Quebec, Canada
  • Chenier, Isabelle, CRCHUM,University of Montreal, Montreal, Quebec, Canada
  • Yamashita, Michifumi, Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Filep, Janos G., Maisonneuve-Rosemont Hosp., Montreal, Quebec, Canada
  • Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States
  • Zhang, Shao-Ling, CRCHUM,University of Montreal, Montreal, Quebec, Canada
  • Chan, John S.D., CRCHUM,University of Montreal, Montreal, Quebec, Canada
Background

We previously showed that tubular deficiency of heterogeneous nuclear ribonucleoprotein F (hnRNPF) results in up-regulation of renal angiotensinogen (Agt) and down-regulation of sodium-glucose co-transporter-2 (SGLT2) in mice. Non-diabetic tubule-specific hnRNPF knockout (FKO) mice developed hypertension and renal fibrosis but had similar blood glucose (BG) levels or glomerular filtration rate (GFR) as control mice. Here, we investigated the effects of FKO in diabetic Akita mice, a murine model of type 1 diabetes.

Methods

FKO mice were generated via cross-breeding of Pax8-Cre mice with floxed hnRNPF mice on a C57BL/6 background. Akita-FKO mice were created by cross-breeding of female FKO mice with male heterozygous Akita mice. Both male and female Akita-FKO mice and Akita control littermates were studied (n=8/group). Body weight (BW), BG, and systolic blood pressure (SBP) were monitored up to age 24 weeks. GFR was measured by inulin-FITC clearance in awake mice; kidneys were processed for histology (PAS, Masson's trichrome, electron microscope).

Results

Akita-FKO mice had better glycemic control, lower kidney weight/BW ratio, and lower GFR/BW ratio than Akita control mice. SBP was significantly higher in male but not in female Akita-FKO mice as compared to Akita. Urinary albumin/creatinine ratio did not differ in the two groups. Renal histology in Akita-FKO mice showed an attenuated glomerulomegaly and tubulointerstitial fibrosis with improved GBM thickness and foot process effacement cf. Akita. Real-time qPCR on kidney cortex confirmed down-regulated expression of SGLT2 and fibrosis marker genes (fibronectin 1, α–smooth muscle actin, collagen 1) and up-regulated Agt expression in Akita-FKO mice cf. Akita.

Conclusion

Kidney hypertrophy and glomerular hyperfiltration were attenuated in Akita-FKO mice, likely due to SGLT2 down-regulation activating tubuloglomerular feedback. The renoprotective effect of SGLT2 down-regulation overcomes the renal injurious effect of Agt when these opposing factors coexist. The Akita-FKO mouse is a unique tool for studying the molecular mechanisms of SGLT2 regulation in diabetes.

Funding

  • Government Support - Non-U.S.