Effects of canagliflozin combined with amiloride or benzamil on bone metabolism in rats with nephrotic syndrome

To investigate the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i)canagliflozin and epithelial sodium channel inhibitor amiloride or benzamil in combination on the bone metabolism in the rats with the nephrotic syndrome (NS) induced by doxorubicin.

In the 49 male SD rats selected, 7 were randomly selected as control group (NG), and 42 were built as adriamycin-induced nephropathy model by injecting adriamycin through the tail vein, and were randomly divided into model group (MG group), canagliflozin group (KG group), benzamil group (BH group), amiloride group (AL group), canagliflozin+benzamil group (KB group) and canagliflozin+amiloride group (KA group), with 7 cases in each group. Each medication group was given intragastric administration according to the body weight of rats regularly every day, NG group and MG group were given equal amount of normal saline, the course of treatment was 6 weeks. The 24-hour urinary protein (24 h-UTP) of each group was detected one day before treatment to verify the successful preparation of the model. At 6 weeks after treatment, the 24 h-UTP, urine sodium (UNa), urinary potassium (UK) levels in urine and the albumin (ALB), triglyceride (TG), cholesterol (TC), low density lipoprotein (LDL), serum calcium (SCa), sodium (SNa), potassium (SK), 25-hydroxyvitamin D (25-OH-D), alkaline phosphatase (ALP), parathyroid hormone (PTH), procollagen type Ⅰ N-terminal propeptide (PINP) and beta C-terminal cross-linked telopeptides of typeⅠ collagen (β-CTX) levels in serum were measured, respectively.

After successful modeling, the levels of 24 h-UTP, TG, TC, LDL and SCa in the MG group were significantly increased, while the levels of ALB, 25-OH-D, ALP, PINP and PTH were significantly decreased (P < 0.05 or P < 0.01). After 6 weeks of drug intervention, the body mass of rats treated with KG alone decreased significantly (P < 0.05). Compared with the MG group, the levels of 24 h-UTP, TC, TG, LDL and SCa were significantly decreased, and the level of ALB was significantly increased in all drug groups when compared to the MG (P < 0.05 or P < 0.01). Compared with the MG group, the levels of 25-OH-D, ALP, PINP and β-CTX in the KA group were significantly increased when compared to the MG (P < 0.05 or P < 0.01). Molding and drug therapy had no impact on levels of UNa, UK, SK and SNa (P>0.05).

Calaglizin alone, benzamil alone, amiloride alone and calaglizin combined with benzamil or amiloride can improve the mass proteinuria, hypoproteinemia and hyperlipidemia in adriamycin-induced NS model rats. The combination of caraglipzin and amiloride has a significant osteogenic or osteoclastic effect, which may play a role in reducing the risk of fracture in NS rats by forming a new osteogenic/osteoclastic balance.