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

T. S. Polhill, S. Saad, P. Poronnik, G. R. Fulcher, C. A. Pollock

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)F268-F273
Number of pages6
JournalAmerican Journal of Physiology - Renal Physiology
Volume287
Issue number2
DOIs
Publication statusPublished - Jul 2004
Externally publishedYes

Keywords

  • matrix turnover
  • kidney fibrosis
  • diabetes mellitus
  • postprandial hyperglycemia
  • CORONARY HEART-DISEASE
  • DEPENDENT DIABETES-MELLITUS
  • TISSUE GROWTH-FACTOR
  • PROTEIN-KINASE-C
  • OXIDATIVE STRESS
  • CELL-PROLIFERATION
  • ENHANCES APOPTOSIS
  • ENDOTHELIAL-CELLS
  • KIDNEY-FUNCTION
  • COMPLICATIONS

Cite this