Vascular endothelial growth factor (VEGF) and VEGF receptors in diabetic nephropathy: Expression studies in biopsies of type 2 diabetic patients

Vascular endothelial growth factor (VEGF) is involved in the pathogenesis o f diabetic retinopathy but its role in diabetic nephropathy is only specula tive sa far. It has been shown that in renal cortex of normal kidneys, glom erular and tubular epithelial cells express VEGF and that VEGF165 is the pr edominant isoform. Two VEGF receptors, KDR (kinase domain region) and Flt-1 (fms-like tyrosine kinase) are coexpressed by glomerular and peritubular c apillary endothelial cells. However, VEGF and VEGF receptors are predominan tly expressed at glomerular level. We recently demonstrated that in type 2 diabetic patients glomerular qualitative and quantitative changes of VEGF m RNA 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 e xpression of VEGF, KDR, Flt-1 and the relationship between the two main typ e of VEGF isoforms, VEGF121 and VEGF165 in the tubulo-interstitium of type 2 diabetic patients. Patients were divided in three category on the basis o f 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 in jury, i.e., more severe tubulo-interstitial and vascular than glomerular ch anges. Comparison between the two cortical compartments revealed that, both in glomeruli and in tubulo-interstitium, VEGF121 isoform exceed VEGF165 wh ile Flt-1 was significantly lower in glomeruli. CIII patients had the lowes t tubulo-interstitial level of VEGF and Flt-1 mRNAs. These results suggest that the transcriptional shifting from VEGF165 to VEGF121 isoform and the u nbalanced Flt-1 expression between tubulo-interstitium and glomeruli could be involved in the pathogenesis of diabetic nephropathy. Furthermore, at le ast in CIII patients, down-regulation of the VEGF-Flt-1 system could be inv olved in the mechanisms leading to tubulointerstitial diabetic lesions.