Failure to confirm a sodium–glucose cotransporter 2 inhibitor‐induced hematopoietic effect in non‐diabetic rats with renal anemia

Abstract

Aims/Introduction: Clinical studies have shown that treatment with inhibitors of sodium-glucose cotransporter 2 (SGLT2) significantly increases the hematocrit in patients with type 2 diabetes. To investigate whether SGLT2 inhibitors directly promote erythropoietin production independently on blood glucose reduction, the hematopoietic effect of the specific SGLT2 inhibitor, luseogliflozin, was examined in non-diabetic rats with renal anemia. Materials and Methods: Renal anemia was induced by treatment with adenine (200 or 600 mg/kg/day, orally for 10 days) in non-diabetic Wistar-Kyoto or Wistar rats, respectively. Luseogliflozin (10 mg/kg bodyweight) or vehicle (0.5% carboxymethyl cellulose) was then administered for 6 weeks. The hematocrit and the hemoglobin (Hb), blood urea nitrogen, plasma creatinine, and plasma erythropoietin levels were monitored. Results: Treatment with adenine decreased the hematocrit and the Hb level, which were associated with increases in the blood urea nitrogen and plasma creatinine levels. In Wistar-Kyoto rats treated with 200 mg/kg/day adenine, administration of luseogliflozin induced glycosuria, but did not change the blood urea nitrogen, plasma creatinine levels, hematocrit, Hb or plasma erythropoietin levels. Similarly, luseogliflozin treatment failed to change the hematocrit or the Hb levels in Wistar rats with renal anemia induced by 600 mg/kg/day of adenine. Plasma erythropoietin concentrations were also not different between luseogliflozin-and vehicle-treated rats. Similarly, in human erythropoietin-producing cells derived from pluripotent stem cells, luseogliflozin treatment did not change the erythropoietin level in the medium. Conclusions: These data suggest that SGLT2 inhibitor fails to exert hematopoietic effects in non-diabetic conditions.

Possible renoprotective mechanisms of SGLT2 inhibitors

“…This decrease was associated with a decreased GFR and increased blood erythropoietin expression and erythrocyte reticulocyte count. In contrast, no such changes were observed in other studies ( 31 , 32 ). Therefore, these data suggest that the effects of SGLT2 inhibitors in promoting erythropoietin production in the kidney differ depending on the pathogenesis of CKD.…”

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models

“…Given this overwhelming evidence, it is surprising that data from preclinical studies in rodents with non-diabetic renal damage, which are inevitable to identify the mechanistic background behind nephroprotection, have so far provided rather inconsistent results. A number of in vivo studies reported no improvement of renal impairment by SGLT2 inhibitors caused by, e.g., 5/6 nephrectomy in rats (Zhang et al, 2016;Rajasekeran et al, 2018), polycystic kidney disease in rats (Kapoor et al, 2015), oxalate-induced nephrocalcinosis in mice (Ma et al, 2017) and adenine-induced fibrosis in rats (Yamazaki et al, 2020). On the contrary, data supporting a renal benefit by SGLT2 inhibition were provided from disease models like ischemia-reperfusion injury (Chang et al, 2016), unilateral ureteric obstruction (Abbas et al, 2018), proteinoverload proteinuria (Cassis et al, 2018), Ang II-dependent hypertension (Castoldi et al, 2020), cyclosporine-A nephropathy (Castoldi et al, 2021), adenine nephropathy (Yamato et al, 2020) and salt-sensitive hypertension in uninephrectomized rats (Kim et al, 2019).…”

Relationship Between SGLT2 Inhibitors and Hemoglobin Levels: A Retrospective Observational Study

“…An increase in Hb levels is also observed in patients with impaired renal function, which may be related to the renoprotective effect of SGLT2 inhibitors. Yamazaki Wistar rats (male, 5 weeks old) and investigated its anemia suppression effects (24). No increase in Hb and Hct levels was observed in renal anemia.…”