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Abstract: FR-OR21

Empagliflozin Blunts Renal Mg2+ Wasting and Restores Distal Tubule Sodium Chloride Cotransporter (NCC) and TRPM6 Expression in Rats with Cisplatin-Induced Hypomagnesemia

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

  • 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • McCormick, James A., Oregon Health & Science University School of Medicine, Portland, Oregon, United States
  • Jesus, Erika Fernandes, Universidade de Sao Paulo, Sao Paulo, Brazil
  • Caetano, Marcos Vinícius, Universidade de Sao Paulo, Sao Paulo, Brazil
  • Luchi, Weverton M., Universidade Federal do Espirito Santo, Vitoria, ES, Brazil
  • Girardi, Adriana C. C., Universidade de Sao Paulo, Sao Paulo, Brazil
Background

The chemotherapeutic agent cisplatin is known to cause hypomagnesemia and renal Mg2+ wasting. Damage to the distal convoluted tubule (DCT), a key site of regulated Mg2+ reabsorption, may contribute. Recent clinical studies suggest that SGLT2 inhibitors increase serum Mg2+ concentration in patients with diabetes. However, the potential therapeutic use of SGLT2 inhibitors in a scenario of cisplatin-induced hypomagnesemia has not been investigated. This study tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) attenuates cisplatin-induced hypomagnesemia in rats through effects on the DCT.

Methods

Male Wistar rats (10 weeks of age) were treated weekly with cisplatin (2.5 mg/kg/or vehicle, i.p.) for five weeks. After three weeks of treatment, cisplatin (Cis) and vehicle-treated (Ctrl) rats were randomized and orally treated or not with EMPA (10 mg/kg/day) for two weeks.

Results

Cis-treated rats developed significant hypomagnesemia (1.42 ± 0.05 vs. 2.19 ± 0.03 mg/dl in Ctrl and 2.23 ± 0.03 mg/dl in Ctrl + EMPA, P < 0.0001) and increased fractional excretion (FE) of Mg2+ compared to control groups (14.3 ± 1.3 vs. 0.48 ± 0.10% in Ctrl and 0.65 ± 0.10% in Ctrl + EMPA, P < 0.0001). EMPA reduced FE Mg (2.2 ± 0.2 vs. 14.3 ± 1.3% vs. P < 0.0001) and restored Mg2+ serum levels in Cis-treated rats (2.21 ± 0.05 mg/dl). The mRNA and protein abundance of NCC and TRPM6 and NCC phosphorylation were reduced in Cis-treated rats and rescued by EMPA. EMPA-treated Ctrl rats displayed higher NCC and TRPM6 mRNA and protein expression and NCC phosphorylation levels than untreated Ctrl. The effects of cisplatin and EMPA on NCC were confirmed using a hydrochlorothiazide (HCTZ) challenge. The natriuretic response to HCTZ in Cis-treated rats was lower and in Ctrl + EMPA higher than the other groups of rats. No difference was found in the natriuretic response to HCTZ between controls and EMPA-treated Cis-rats. Remarkably, immunohistochemistry suggested that EMPA reversed Cis-induced DCT injury.

Conclusion

Empagliflozin blunts renal Mg2+ wasting and restores serum Mg2+ concentration in cisplatin-treated rats. The effects of the SGLT2 inhibitor were associated with reversal of DCT injury, rescue of expression of TRPM6, NCC, and phosphorylated NCC, and normalization of NCC activity.

Funding

  • NIDDK Support