Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats

Abstract

This study examined the effect of long-term control of hyperglycemia with a new sodium glucose cotransporter 2 inhibitor, luseogliflozin, given alone or in combination with lisinopril on the progression of renal injury in the T2DN rat model of type 2 diabetic nephropathy. Chronic treatment with luseogliflozin (10 mg/kg/day) produced a sustained increase in glucose excretion and normalized blood glucose and glycosylated hemoglobin levels to the same level as seen in the rats treated with insulin. It had no effect on blood pressure. In contrast, lisinopril (10 mg/kg/day) reduced mean blood pressure from 140 to 113 mmHg. Combination therapy significantly reduced blood pressure more than that seen in the rats treated with lisinopril. T2DN rats treated with vehicle exhibited progressive proteinuria, a decline in glomerular filtration rate (GFR), focal glomerulosclerosis, renal fibrosis, and tubular necrosis. Control of hyperglycemia with luseogliflozin prevented the fall in GFR and reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis. In contrast, control of hyperglycemia with insulin had no effect on the progression of renal disease in T2DN rats. Reducing blood pressure with lisinopril prevented the fall in GFR and reduced proteinuria and the degree of glomerular injury and tubular necrosis. Combination therapy reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis to a greater extent than administration of either drug alone. These results suggest that control of hyperglycemia with luseogliflozin slows the progression of diabetic nephropathy more than that seen with insulin, and combination therapy is more renoprotective than administration of either compound alone.

Fig. 1.

Structure of luseogliflozin.

Fig. 2.

Effects of luseogliflozin, lisinopril, combination therapy, and insulin on body weight (A), daily food intake (B), urinary glucose excretion (C), and daily water intake (D) in T2DN rats. Numbers in parentheses indicate the number of rats studied per group. *Indicates a significant difference from the corresponding value in vehicle-treated rats. †Indicates a significant difference from the corresponding value in luseogliflozin-treated rats. ‡Indicates a significant difference from the corresponding value in lisinopril-treated rats.

Fig. 3.

Effects of luseogliflozin, lisinopril, combination therapy, and insulin on nonfasting blood glucose levels (A), HbA1c levels (B), and plasma insulin levels (C) in T2DN rats. Numbers in parentheses indicate the number of rats studied per group. *Indicates a significant difference from the corresponding value in vehicle-treated rats. †Indicates a significant difference from the corresponding value in luseogliflozin-treated rats. ‡Indicates a significant difference from the corresponding value in lisinopril-treated rats.

Fig. 4.

Effects of luseogliflozin, lisinopril, combination therapy, and insulin on systolic blood pressure (A), mean blood pressure (B), diastolic blood pressure (C), and urinary protein excretion (D) in T2DN rats. Numbers in parentheses indicate the number of rats studied per group. *Indicates a significant difference from the corresponding value in vehicle-treated rats. †Indicates a significant difference from the corresponding value in luseogliflozin-treated rats. ‡Indicates a significant difference from the corresponding value in lisinopril-treated rats.

Fig. 5.

Effects of 3-month chronic treatment with luseogliflozin, lisinopril, combination therapy, and insulin on glomerular filtration rate (A), renal blood flow (B), mean arterial pressure (C), and renal vascular resistance (D) in 17-month-old T2DN rats. Numbers in parentheses indicate the number of rats studied per group. kwt, Kidney weight. #Indicates a significant difference from the corresponding values in 14-month-old T2DN rats. *Indicates a significant difference from the corresponding value in vehicle-treated rats. †Indicates a significant difference from the corresponding value in luseogliflozin-treated rats.

Fig. 6.

Representative microphotographs of the renal cortex (200×) and medulla (100×) stained with Masson’s trichrome in 17-month-old T2DN rats treated with vehicle, luseogliflozin, lisinopril, combination therapy, and insulin.

Fig. 7.

Effects of 3-month chronic treatment with luseogliflozin, lisinopril, combination therapy, and insulin on glomerular injury score (A), renal cortex fibrosis (B), glomerular diameter (C), and urinary nephrin excretion (D) in 17-month-old T2DN rats. Numbers in parentheses indicate the number of glomeruli or areas scored and the number of rats studied per group. #Indicates a significant difference from the corresponding values in 14-month-old T2DN rats. *Indicates a significant difference from the corresponding value in vehicle-treated rats. †Indicates a significant difference from the corresponding value in luseogliflozin-treated rats. ‡Indicates a significant difference from the corresponding value in lisinopril-treated rats.

Fig. 8.

Effects of 3-month chronic treatment with luseogliflozin, lisinopril, combination therapy, and insulin on renal outer medullary fibrosis (blue staining of collagen and fibronectin) (A) and red-stained tubular protein casts an index of tubular necrosis (B) in 17-month-old T2DN rats. Numbers in parentheses indicate the number of areas scored and the number of rats studied per group. *Indicates a significant difference from the corresponding value in vehicle-treated rats. †Indicates a significant difference from the corresponding value in luseogliflozin-treated rats. ‡Indicates a significant difference from the corresponding value in lisinopril-treated rats.