Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat.
Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and (125)I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function.
Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
Christine
C
Maric-Bilkan
Elizabeth R
ER
Flynn
Alejandro R
AR
Chade
D000792:Angiography / Q000379:methods; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D005919:Glomerular Filtration Rate / Q000502:physiology; D007668:Kidney / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008833:Microcirculation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D055114:X-Ray Microtomography
D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat