Short-term peaks in glucose promote renal fibrogenesis independently of total glucose exposure.
Postprandial hyperglycemia is implicated as a risk factor predisposing to vascular complications. This study was designed to assess recurrent short-term increases in glucose on markers of renal fibrogenesis. Human renal cortical fibroblasts were exposed to fluctuating short-term (2 h) increases to 15 mM d-glucose, three times a day over 72 h, on a background of 5 mM d-glucose. To determine whether observed changes were due to fluctuating osmolality, identical experiments were undertaken with cells exposed to l-glucose. Parallel experiments were performed in cells exposed to 5 mM d-glucose and constant exposure to either 15 or 7.5 mM d-glucose. Fluctuating d-glucose increased extracellular matrix, as measured by proline incorporation (P < 0.05), collagen IV (P < 0.005), and fibronectin production (P < 0.001), in association with increased tissue inhibitor of matrix metalloproteinase (MMP) (P < 0.05). Sustained exposure to 15 mM d-glucose increased fibronectin (P < 0.001), in association with increased MMP-2 (P = 0.01) and MMP-9 activity (P < 0.05), suggestive of a protective effect on collagen matrix accumulation. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA was increased after short-term (90 min) exposure to 15 mM glucose (P < 0.05) and after 24-h exposure to 7.5 mM ? (P < 0.05). Normalization of TGF-beta(1) secretion occurred within 48 h of constant exposure to an elevated glucose. Fluctuating l-glucose also induced TGF-beta(1) mRNA and a profibrotic profile, however, to a lesser extent than observed with exposure to fluctuating d-glucose. The results suggest that exposure to fluctuating glucose concentrations increases renal interstitial fibrosis compared with stable elevations in d-glucose. The effects are, in part, due to the inherent osmotic changes.
Polhill
T S
TS
Renal Research Group, Kolling Institute, Royal North Shore Hospital, University of Sydney, St. Leonards, New South Wales, Australia.
Saad
S
S
Poronnik
P
P
Fulcher
G R
GR
Pollock
C A
CA
D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007672:Kidney Cortex / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D001786:Blood Glucose; D024141:Collagen Type IV; D005353:Fibronectins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D011392:Proline; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose