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Abstract: TH-PO854

Renal SGLT2 mRNA Expression in Diabetic and Non-Diabetic Kidney Disease in Humans

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sridhar, Vikas, University of Toronto, Toronto, Ontario, Canada
  • Ambinathan, Jaya Prakash Nath, University of Toronto, Toronto, Ontario, Canada
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Bjornstad, Petter, Children's Hospital Colorado, Aurora, Colorado, United States
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Cherney, David, University of Toronto, Toronto, Ontario, Canada
  • Reich, Heather N., University of Toronto, Toronto, Ontario, Canada

Group or Team Name

  • ERCB and NEPTUNE groups
Background

In the setting of diabetes, intraglomerular hypertension is associated with chronic kidney disease (CKD) progression, in part through sodium-glucose cotransporter 2 (SGLT2)-mediated suppression of tubuloglomerular feedback (TGF). Pharmacological inhibition of SGLT2 activates TGF and reduces CKD progression in the setting of diabetes, and is being examined as a renal protection strategy in non-diabetic CKD trials. Despite interest in this field and ongoing trials, levels of renal SGLT2 mRNA expression in human health and disease have not yet been fully examined. Our aim was to quantify human renal SGLT2 mRNA expression in healthy controls (HC), in glomerulonephritis subtypes (GN) and in patients with diabetic kidney disease (DKD).

Methods

SGLT2 mRNA expression was quantified and compared in HC vs. GN vs. DKD in the European Renal cDNA Bank (ERCB). Second, renal SGLT2 mRNA expression from the Nephrotic Syndrome Study Network (NEPTUNE) was analyzed using biopsies from patients with membranous nephropathy (MN), minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). mRNA was obtained by microdissection of tubulointerstitial compartments from adult renal biopsies and processed using a microarray platform.

Results

In ERCB (n=166), SGLT2 mRNA expression was 9.42±0.50, 9.19±0.50 and 8.85±0.64 in HC, GN and DKD respectively (p=0.0044). SGLT2 mRNA expression was higher in HC vs. DKD and GN vs. DKD (p<0.05 for both). In NEPTUNE (n=121), there were no mRNA expression differences across GN subtypes (MN vs. MCD vs. FSGS vs. IgAN). In NEPTUNE patients with GN, eGFR (r= 0.32, p<0.001) was positively correlated with SGLT2 mRNA expression and interstitial fibrosis was negatively correlated with SGLT2 expression (r=-0.23, p<0.01). No relationships were seen with proteinuria.

Conclusion

SGLT2 mRNA expression is lower in patients with DKD compared to HC or GN, and is related to the degree of interstitial fibrosis in GN patients. In light of protective effects on DKD outcomes in clinical trials despite apparently having the lowest SGLT2 mRNA expression, further studies are required to better understand the relationship between SGLT2 protein levels and/or activity and CKD outcomes in humans.