Short-term peaks in glucose promote renal fibrogenesis independently of total glucose exposure

• Published in: American journal of physiology. Renal physiology 2004-08, Vol.56 (2), p.F268-F273
• Main Authors: POLHILL, T. S, SAAD, S, PORONNIK, P, FULCHER, G. R, POLLOCK, C. A
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diabetes; Fundamental and applied biological sciences. Psychology; Glucose; Kidneys; Vertebrates: urinary system
• ISSN: 1931-857X; 1522-1466

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-beta1 (TGF-beta1) 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 secretion occurred within 48 h of constant exposure to an elevated glucose. Fluctuating L-glucose also induced TGF-beta1 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. [PUBLICATION ABSTRACT]