SGLT2 Inhibitors Blunt Kidney Magnesium Wasting in Acute Cisplatin-Induced Hypomagnesemia with Effects on the TAL and DCT

Background: Cisplatin, a chemotherapeutic agent, induces kidney magnesium wasting and hypomagnesemia. Recent studies suggest that SGLT2 inhibitors elevate serum magnesium concentration in patients with or without diabetes. We hypothesized that the SGLT2 inhibitor empagliflozin attenuates acute cisplatin-induced hypomagnesemia by acting on the thick ascending limb (TAL) and distal convoluted tubule (DCT), key sites of magnesium reabsorption. Methods: Adult male Wistar rats received weekly treatments of cisplatin (2.5 mg/kg) or saline (vehicle) for five weeks. After three weeks, rats were randomized to receive empagliflozin (10 mg/kg/day) or water (vehicle) for the next fifteen days. Results: Cisplatin-treated rats developed significant hypomagnesemia with increased fractional excretion of magnesium (FEMg 2+ ). Empagliflozin treatment reduced FEMg 2+ and restored serum magnesium levels. In the TAL, cisplatin-treated rats had higher NKCC2 abundance but lower phosphorylated NKCC2 and claudin-16 levels than empagliflozin-treated cisplatin rats, whose protein levels were similar to controls. In contrast, claudin-19 abundance in the TAL was higher in cisplatin-treated rats than in controls and unaffected by empagliflozin treatment. In the DCT, cisplatin-treated rats displayed reduced abundance of the NaCl cotransporter (NCC), the magnesium channel TRPM6, and NCC phosphorylation, all of which were rescued by empagliflozin. Unexpectedly, cisplatin-treated rats exhibited higher mRNA expression and protein abundance of TRPM7 compared to empagliflozin-treated cisplatin rats, whose levels were similar to controls. Diuretic challenge tests with furosemide or hydrochlorothiazide confirmed reduced NKCC2 and NCC activity in cisplatin-treated rats. However, the natriuretic response to furosemide or hydrochlorothiazide did not differ between control and empagliflozin-treated cisplatin rats. Immunohistochemistry suggested that empagliflozin reversed cisplatin-induced DCT remodeling. Conclusions: Empagliflozin reduces kidney magnesium wasting and restores serum magnesium in cisplatin-treated rats, likely through reversing NKCC2 inhibition and claudin-16 downregulation in the TAL while normalizing NCC function and restoring TRPM6 expression in the DCT.