Sharkovska Yuliya, Reichetzeder Christoph, Alter Markus, Tsuprykov Oleg, Bachmann Sebastian, Secher Thomas, Klein Thomas, Hocher Berthold
aInstitute of Vegetative Anatomy, Charite Universitätsmedizin Berlin bCenter for Cardiovascular Research, Institute of Pharmacology, Charité cUniversity of Potsdam, Potsdam dDepartment of Nephrology, Charité Campus Benjamin Franklin, Berlin, Germany eGubra, Copenhagen, Denmark fBoehringer Ingelheim, Biberach, Germany.
J Hypertens. 2014 Nov;32(11):2211-23; discussion 2223. doi: 10.1097/HJH.0000000000000328.
Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear.
This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8).
Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well.
Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.
尽管4型二肽基肽酶（DPP-4）抑制剂对血糖水平有有益作用，但其对糖尿病肾病的影响仍不清楚。
本研究检测了DPP-4抑制剂利那格列汀对2型糖尿病模型db/db小鼠的长期肾脏保护作用。将结果与依那普利阻断肾素-血管紧张素系统的已知有益作用进行比较。10周龄雄性糖尿病db/db小鼠分别用溶剂（n = 10）、3 mg利那格列汀/千克/天（n = 8）或20 mg依那普利/千克/天（n = 10）治疗3个月。用溶剂处理的杂合子db/m小鼠作为健康对照（n = 8）。
利那格列汀和依那普利对糖尿病db/db小鼠的糖代谢参数或血压均无显著影响。然而，利那格列汀治疗可降低蛋白尿并减轻肾脏损伤。此外，足细胞标志物足突细胞粘附分子的表达恢复正常。我们还通过免疫荧光分析了人肾活检组织中DPP-4的表达，检测到糖尿病肾病患者肾小球中DPP-4上调，这表明我们的发现可能也与人类肾脏疾病相关。
DPP-4抑制剂利那格列汀治疗以不依赖血糖和不依赖血压的方式延缓糖尿病肾病损伤的进展。观察到的效果可能是由于足细胞损伤的减轻和肌成纤维细胞转化的抑制。
