Velho Gilberto, Ragot Stéphanie, Mohammedi Kamel, Gand Elise, Fraty Mathilde, Fumeron Frédéric, Saulnier Pierre-Jean, Bellili-Munoz Naima, Bouby Nadine, Potier Louis, Alhenc-Gelas François, Marre Michel, Hadjadj Samy, Roussel Ronan
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
INSERM, Centre d'Investigation Clinique (CIC) 1402, Poitiers, France UFR de Médecine et Pharmacie, Université de Poitiers, Poitiers, France.
Diabetes. 2015 Sep;64(9):3262-72. doi: 10.2337/db14-1852. Epub 2015 May 6.
Production of adrenomedullin (ADM), a vasodilator peptide, increases in response to ischemia and hypoxia in the vascular wall and the kidney. This may be an adaptive response providing protection against organ damage. We investigated the hypothesis that ADM has a nephroprotective effect in two prospective cohorts of patients with type 2 diabetes recruited in France. The highest tertile of plasma MR-proADM (a surrogate for ADM) concentration at baseline was associated with the risk of renal outcomes (doubling of plasma creatinine concentration and/or progression to end-stage renal disease) during follow-up in both cohorts. Four SNPs in the ADM gene region were associated with plasma MR-proADM concentration at baseline and with eGFR during follow-up in both cohorts. The alleles associated with lower eGFR were also associated with lower plasma MR-proADM level. In conclusion, plasma MR-proADM concentration was associated with renal outcome in patients with type 2 diabetes. Our data suggest that the ADM gene modulates the genetic susceptibility to nephropathy progression. Results are consistent with the hypothesis of a reactive rise of ADM in diabetic nephropathy, blunted in risk alleles carriers, and with a nephroprotective effect of ADM. A possible therapeutic effect of ADM receptor agonists in diabetic renal disease would be worth investigating.
血管舒张肽肾上腺髓质素（ADM）的生成会因血管壁和肾脏的缺血及缺氧而增加。这可能是一种适应性反应，可提供针对器官损伤的保护作用。我们在法国招募的两个2型糖尿病患者前瞻性队列中研究了ADM具有肾保护作用这一假设。在两个队列的随访期间，基线时血浆MR-proADM（ADM的替代指标）浓度最高三分位数与肾脏结局风险（血浆肌酐浓度翻倍和/或进展至终末期肾病）相关。ADM基因区域的四个单核苷酸多态性（SNP）与两个队列基线时的血浆MR-proADM浓度以及随访期间的估算肾小球滤过率（eGFR）相关。与较低eGFR相关的等位基因也与较低的血浆MR-proADM水平相关。总之，血浆MR-proADM浓度与2型糖尿病患者的肾脏结局相关。我们的数据表明，ADM基因调节肾病进展的遗传易感性。结果与糖尿病肾病中ADM反应性升高的假设一致，在风险等位基因携带者中这种升高减弱，并且与ADM的肾保护作用一致。ADM受体激动剂在糖尿病肾病中可能的治疗作用值得研究。
