IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
PLoS One. 2013 Aug 14;8(8):e70775. doi: 10.1371/journal.pone.0070775. eCollection 2013.
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF) and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE) inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics.
成纤维细胞生长因子 23（FGF23）是一种主要由骨骼产生的磷调节激素，通过 FGF 受体和 Klotho 在肾脏中发挥作用。在这里，我们使用 2 型糖尿病肾病模型研究了肾脏是否在肾脏疾病期间成为 FGF23 的另一个来源。在 2、4、6 和 8 月龄的 Zucker 糖尿病肥胖（ZDF）和对照瘦鼠中评估了肾脏中 FGF23 和 Klotho 的表达。为了评估血管紧张素转换酶（ACE）抑制剂在该模型中的肾保护作用是否与 FGF23 和 Klotho 的变化相关，从 4 月龄（出现蛋白尿时）开始，ZDF 大鼠接受雷米普利治疗至 8 月龄。瘦鼠和 2 月龄的 ZDF 大鼠的肾脏中均未检测到 FGF23 mRNA。在 4 月龄时，糖尿病大鼠的肾脏中可以检测到 FGF23，此后显著增加。FGF23 蛋白定位于近端和远端肾小管。随着时间的推移，ZDF 大鼠的肾脏 Klotho mRNA 和蛋白减少。随着肾脏疾病的进展，血清磷酸盐水平与肾小球滤过分数磷排泄率的下降平行增加。雷米普利限制蛋白尿和肾脏损伤，减弱了肾脏 FGF23 的上调并改善了 Klotho 的表达。雷米普利使血清磷酸盐水平正常化，并趋于增加肾小球滤过分数磷排泄率。这些数据表明，在进行性肾脏疾病期间，肾脏是 FGF23 产生的部位，这种产生受到 ACE 抑制的限制。在糖尿病中通过药理学手段干预 FGF23 和磷之间的微妙平衡可能具有临床意义。
