Clinica Nefrologica, Az. Ospedaliera San Gerardo, Dipartimento di Scienze della Salute, Università degli Studi di Milano-Bicocca, Monza, Italy.
Am J Nephrol. 2013;37(1):65-73. doi: 10.1159/000346116. Epub 2013 Jan 11.
Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis.
Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5).
Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril.
Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.
糖尿病肾病是终末期肾病的主要病因。N-乙酰-丝氨酰-天门冬酰-赖氨酰-脯氨酸（Ac-SDKP）是血管紧张素转换酶（ACE）水解的一种生理四肽，在高血压、心力衰竭和肾病的实验模型中具有抗纤维化作用。本研究旨在评估 Ac-SDKP 在糖尿病肾病中的作用，以及与 ACE 抑制剂单独使用相比，Ac-SDKP 对肾脏纤维化发展的潜在附加作用。
通过单次腹腔注射链脲佐菌素诱导 28 只 Sprague-Dawley 大鼠产生糖尿病。对照组（n=10）仅接受缓冲液。11 只糖尿病大鼠给予 ACE 抑制剂（雷米普利，3mg/kg/天）。2 个月后，7 只糖尿病大鼠和 6 只接受雷米普利治疗的糖尿病大鼠通过渗透微型泵给予 Ac-SDKP（1mg/kg/天）8 周。相应的假处理大鼠（糖尿病大鼠，n=10，和雷米普利治疗的糖尿病大鼠，n=5）给予渗透微型泵输送生理盐水。
与对照组相比，糖尿病大鼠血糖水平显著升高，尿白蛋白排泄量和肾脏纤维化增加，肾小球足细胞蛋白 Nephrin 表达减少。Ac-SDKP 给药可显著降低糖尿病大鼠的肾脏纤维化，而对尿白蛋白排泄无明显影响。雷米普利治疗可显著减少蛋白尿和肾脏纤维化，并恢复肾小球 Nephrin 表达。与单独使用雷米普利相比，同时给予 Ac-SDKP 可进一步降低肾脏纤维化，而对雷米普利的抗蛋白尿作用无改善。
Ac-SDKP 给药可减轻糖尿病肾病中的肾脏纤维化。与 ACE 抑制治疗联合使用 Ac-SDKP 可改善 ACE 抑制治疗单独使用时的肾脏纤维化减轻程度，表明这种药物联合治疗在糖尿病肾病中有有益作用。
