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Abstract: FR-PO359

Direct Effects of SGLT2 Inhibitors on Proximal Tubule Function

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Albalawy, Wafaa N., University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States
  • Youm, Elynna B., University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States
  • Shipman, Katherine E., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
  • Long, Kimberly R., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
  • Rbaibi, Youssef, University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
  • Baty, Catherine J., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
  • Mutchler, Stephanie, University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
  • Kashlan, Ossama B., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
  • Weisz, Ora A., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
Background

Sodium glucose transporter 2 inhibitors (SGLT2i) have been shown to have cardiorenal protection in patients with and without T2DM. Inhibition of proximal tubule (PT) sodium/hydrogen exchanger type 3 (NHE3), which is known to regulate endocytosis and fluid transport in the PT, has been suggested to contribute to the SGLT2i renoprotective benefits. Also, some SGLT2i have been demonstrated to activate AMPK. However, the underlying mechanisms behind the beneficial effects of SGLT2i are unknown. To circumvent the challenges of untangling the direct effects of SGLT2i on PT function in vivo, we examined the effects of gliflozins in a well-characterized and highly differentiated opossum kidney (OK) cell culture model of the PT S1 segment.

Methods

The effect of gliflozins vs NHE3 inhibitor S3226 on albumin uptake and fluid transport was quantified in OK cells. Endosomal pH was measured by fluorescence ratio imaging in OK cells treated with cana vs S3226. Effects of gliflozins, S3226, and AMPK pathway perturbants were determined by immunoblotting. 10-week-old male C57BL/6 mice were given cana or empa by oral gavage daily following vehicle gavage. Urine was collected via metabolic cages at baseline and after 24h and 48h. Creatinine and albumin were measured by ELISA.

Results

A subset of SGLT2i (cana and tofo, but not empa) impaired endocytosis and fluid transport in a dose-dependent and glucose-independent manner. Surprisingly, SGLT2i did not recapitulate the effect of S3226 on NHE3 phosphorylation or endosomal pH. Treatment with cana but not empa caused a rapid increase in AMPK phosphorylation and a reduction in phospho-S6 ribosomal protein (pS6), a downstream target of mTOR. These effects were observed at concentrations comparable to plasma levels in humans on standard doses of cana. In our mouse study, both treatment conditions led to increased urine volume compared to baseline, cana treated mice urinated significantly more than emp treated mice.

Conclusion

Differential effects of SGLT2i on fluid transport and albumin uptake in OK cell monolayers may be mediated by off-target effects on AMPK/mTOR activity. These off-target effects could contribute to the differences we observed in mice treated for short periods with cana vs empa, and could impact the renal protective mechanisms of SGLT2i in humans.