Bortoloso E, Del Prete D, Gambaro G, Dalla Vestra M, Sailer A, Baggio B, Antonucci F, Fioretto P, Anglani F
Division of Nephrology University of Padova, Italy.
Ren Fail. 2001 May-Jul;23(3-4):483-93. doi: 10.1081/jdi-100104731.
Vascular endothelial growth factor (VEGF) is involved in the pathogenesis of diabetic retinopathy but its role in diabetic nephropathy is only speculative so far. It has been shown that in renal cortex of normal kidneys, glomerular and tubular epithelial cells express VEGF and that VEGF 165 is the predominant isoform. Two VEGF receptors, KDR (kinase domain region) and Flt-1 (fms-like tyrosine kinase) are co-expressed by glomerular and peritubular capillary endothelial cells. However, VEGF and VEGF receptors are predominantly expressed at glomerular level. We recently demonstrated that in type 2 diabetic patients glomerular qualitative and quantitative changes of VEGF mRNA expression are associated with functional and structural renal changes. In the present work we focused on the tubulo-interstitial compartment; by reverse transcription/polymerase chain reaction (RT/PCR) we evaluated the expression of VEGF, KDR, Flt-1 and the relationship between the two main type of VEGF isoforms, VEGF121 and VEGF165 in the tubulo-interstitium of type 2 diabetic patients. Patients were divided in three category on the basis of renal structure pattern: CI, with normal or near normal renal structure; CII, with glomerular and tubulo-interstitial lesions occurring in parallel (typical diabetic nephropathology); CIII, with atypical pattern of renal injury, i.e., more severe tubulo-interstitial and vascular than glomerular changes. Comparison between the two cortical compartments revealed that, both in glomeruli and in tubulo-interstitium. VEGF121 isoform exceed VEGF165 while Flt-1 was significantly lower in glomeruli. CIII patients had the lowest tubulo-interstitial level of VEGF and Flt-1 mRNAs. These results suggest that the transcriptional shifting from VEGF165 to VEGF121 isoform and the unbalanced FIt-1 expression between tubulo-interstitium and glomeruli could be involved in the pathogenesis of diabetic nephropathy. Furthermore, at least in CIII patients, down-regulation of the VEGF-Flt-1 system could be involved in the mechanisms leading to tubulointerstitial diabetic lesions.
血管内皮生长因子（VEGF）参与糖尿病视网膜病变的发病机制，但迄今为止其在糖尿病肾病中的作用仍只是推测。研究表明，在正常肾脏的肾皮质中，肾小球和肾小管上皮细胞表达VEGF，且VEGF 165是主要的异构体。两种VEGF受体，即激酶结构域区域（KDR）和fms样酪氨酸激酶（Flt-1），在肾小球和肾小管周围毛细血管内皮细胞中共同表达。然而，VEGF和VEGF受体主要在肾小球水平表达。我们最近证明，在2型糖尿病患者中，VEGF mRNA表达的肾小球定性和定量变化与肾脏的功能和结构变化相关。在本研究中，我们聚焦于肾小管间质部分；通过逆转录/聚合酶链反应（RT/PCR），我们评估了2型糖尿病患者肾小管间质中VEGF、KDR、Flt-1的表达以及两种主要VEGF异构体VEGF121和VEGF165之间的关系。根据肾脏结构模式，将患者分为三类：CI，肾脏结构正常或接近正常；CII，肾小球和肾小管间质病变同时出现（典型的糖尿病肾病病理）；CIII，肾脏损伤模式不典型，即肾小管间质和血管病变比肾小球病变更严重。两个皮质部分之间的比较显示，无论是在肾小球还是在肾小管间质中，VEGF121异构体均超过VEGF165，而Flt-1在肾小球中显著更低。CIII组患者的肾小管间质VEGF和Flt-1 mRNA水平最低。这些结果表明，从VEGF165异构体到VEGF121异构体的转录转变以及肾小管间质和肾小球之间Flt-1表达的失衡可能参与糖尿病肾病的发病机制。此外，至少在CIII组患者中，VEGF-Flt-1系统的下调可能参与导致肾小管间质糖尿病病变的机制。
