Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy.
Dipartimento Di Scienze Radiologiche, Oncologiche E Anatomopatologiche, Istituto Di Anatomia Patologica Sapienza Universita' Di Roma, Roma, Italy.
Acta Diabetol. 2021 Aug;58(8):1059-1070. doi: 10.1007/s00592-021-01681-2. Epub 2021 Mar 24.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, are nephroprotective in case of diabetes, but whether a similar beneficial effect may be detectable also in case of chronic non-diabetic kidney diseases remains still unknown. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, on the progression of cyclosporine nephropathy, in the absence of diabetes.
Sprague Dawley rats (n = 27) have been fed with low-salt diet starting 10 days before the beginning and finished at the end of the experimental period. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection, n = 8) and CsA plus empagliflozin (Empa, 10 mg/kg/day, per os, n = 7) were administered for 4 weeks. The control groups were treated with placebo (Control, n = 7) or empagliflozin (Control + Empa, n = 5). Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental period. At the end of the experimental protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages), type I and type IV collagen expression, and tyrosine hydroxylase expression, used as marker of sympathetic nerve activity.
CsA-treated rats showed a significant increase (p < 0.01) in blood pressure, which was reduced by administration of empagliflozin (p < 0.05). CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p < 0.05), renal inflammatory infiltrates (p < 0.05), type I and type IV collagen expression (p < 0.01), and tyrosine hydroxylase expression (p < 0.01) as compared to the control rats and control + Empa-treated rats. Treatment with empagliflozin in CsA-treated rats reduced glomerular (p < 0.01) and tubulo-interstitial fibrosis (p < 0.05), type I and type IV collagen expression (p < 0.01), inflammatory cell infiltration (p < 0.01) and tyrosine hydroxylase expression (p < 0.05), as compared to rats treated with CsA.
Empagliflozin administration caused a reduction in blood pressure in CsA-treated rats and showed a protective effect on CsA nephropathy by decreasing renal fibrosis, type I and type IV collagen expression, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that empagliflozin promotes nephroprotection also in non-diabetic kidney disease.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂是一种新型抗糖尿病药物，在糖尿病患者中具有肾脏保护作用，但在慢性非糖尿病肾病患者中是否也能检测到类似的有益作用仍不清楚。本研究旨在评估 SGLT-2 抑制剂恩格列净在没有糖尿病的情况下对环孢素肾病进展的影响。
27 只 Sprague Dawley 大鼠在实验开始前 10 天开始食用低钠饮食，并在实验结束时结束。环孢素 A（CsA，15mg/kg/天，腹腔注射，n=8）和 CsA 加恩格列净（Empa，10mg/kg/天，口服，n=7）给药 4 周。对照组给予安慰剂（Control，n=7）或恩格列净（Control+Empa，n=5）治疗。在实验开始和结束时使用体积描记法测量血压。在实验方案结束时，切除肾脏进行肾纤维化的组织形态计量学分析和炎症浸润（单核细胞/巨噬细胞）、I 型和 IV 型胶原表达以及酪氨酸羟化酶表达的免疫组织化学评估，酪氨酸羟化酶表达用作交感神经活性的标志物。
CsA 治疗的大鼠血压显著升高（p<0.01），恩格列净给药可降低血压（p<0.05）。与对照组和 Control+Empa 治疗组相比，CsA 给药导致肾小球和肾小管间质纤维化（p<0.05）、肾炎症浸润（p<0.05）、I 型和 IV 型胶原表达（p<0.01）和酪氨酸羟化酶表达（p<0.01）增加。与 CsA 治疗组相比，CsA 治疗大鼠中恩格列净治疗可降低肾小球（p<0.01）和肾小管间质纤维化（p<0.05）、I 型和 IV 型胶原表达（p<0.01）、炎症细胞浸润（p<0.01）和酪氨酸羟化酶表达（p<0.05）。
恩格列净给药可降低 CsA 治疗大鼠的血压，并通过降低肾纤维化、I 型和 IV 型胶原表达、巨噬细胞浸润和酪氨酸羟化酶表达，对 CsA 肾病发挥保护作用。这些数据表明，恩格列净在非糖尿病肾病中也能促进肾脏保护。
