Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street Jackson, MS 39216, USA.
J Pharmacol Exp Ther. 2013 Jun;345(3):464-72. doi: 10.1124/jpet.113.203869. Epub 2013 Mar 14.
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.
本研究考察了新型钠-葡萄糖共转运蛋白 2 抑制剂卢格列净单独或与赖诺普利联合用于控制长期高血糖对 2 型糖尿病肾病（T2DN）大鼠模型肾损伤进展的影响。卢格列净（10mg/kg/天）的慢性治疗可持续增加葡萄糖排泄，并将血糖和糖化血红蛋白水平正常化至与胰岛素治疗组相同的水平。它对血压没有影响。相比之下，赖诺普利（10mg/kg/天）可将平均血压从 140mmHg 降低至 113mmHg。联合治疗可显著降低血压，降幅大于赖诺普利治疗组。给予载体的 T2DN 大鼠表现出进行性蛋白尿、肾小球滤过率（GFR）下降、局灶性肾小球硬化、肾纤维化和肾小管坏死。用卢格列净控制高血糖可防止 GFR 下降并减轻肾小球损伤、肾纤维化和肾小管坏死的程度。相比之下，用胰岛素控制高血糖对 T2DN 大鼠的肾脏疾病进展没有影响。用赖诺普利降低血压可防止 GFR 下降和蛋白尿以及肾小球损伤和肾小管坏死的程度。联合治疗可更大程度地减轻肾小球损伤、肾纤维化和肾小管坏死的程度，优于单独使用任何一种药物。这些结果表明，与胰岛素相比，用卢格列净控制高血糖可更有效地减缓糖尿病肾病的进展，联合治疗比单独使用任何一种药物更具肾脏保护作用。
