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1 Department of Medicine, Renal Research Group, Kolling Institute, University of Sydney, St. Leonards, Sydney, 2065, New South Wales, Australia
2 Department of Medicine, Renal Research Group, Kolling Institute, University of Sydney, St. Leonards, Sydney, 2065, New South Wales, Australia; School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, 4072, Queensland, Australia
3 Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Sydney, 2065, New South Wales, Australia
* To whom correspondence should be addressed. E-mail: carpol{at}med.usyd.edu.au.
Background: Post-prandial hyperglycaemia is implicated as a risk factor predisposing to vascular
complications. This study was designed to assess effects of recurrent short-term increases in glucose on markers of renal fibrogenesis.
Methods: Human renal cortical fibroblasts were exposed to fluctuating short-term (2 hour) increases to 15 mM D-glucose, 3 times a day over 72 hours, 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 mM or 7.5 mM D-glucose.
Results: 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 (P < 0.05). Sustained exposure to 15 mM D-glucose increased fibronectin (P < 0.001), in association with increased matrix metalloproteinase (MMP)-2 (P = 0.01) and MMP-9 activity (P < 0.05), suggestive of a protective effect on collagen matrix accumulation. Transforming growth factor 
1 (TGF1) mRNA was increased after short term (90 minute) exposure to 15 mM glucose (P < 0.05), and after 24 hour exposure to 7.5 mM (P < 0.05). Normalization of TGF1 secretion occurred within 48 hours of constant exposure to an elevated glucose. Fluctuating L-glucose also induced TGF1 mRNA and a pro-fibrotic profile, however to a lesser extent than observed with exposure to
fluctuating D-glucose.
Conclusions: The results suggest that exposure to fluctuating glucose concentrations increases renal interstitial fibrosis when compared to stable elevations in D-glucose. The effects are in part due to the inherent osmotic changes.
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