4.7 Article

Susceptibility of renal fibrosis in diabetes: Role of hypoxia inducible factor-1

Journal

FASEB JOURNAL
Volume 36, Issue 8, Pages -

Publisher

WILEY
DOI: 10.1096/fj.202200845R

Keywords

diabetic kidney disease; fibrosis; HIF-1; high glucose

Funding

  1. Department of Veterans Affairs of USA [1TK6BX005236, I01 BX000319]
  2. National Institutes of Health of USA [5R01DK058831, 5R01DK087843]
  3. National Natural Science Foundation of China (NSFC) [81873595, 81800681]
  4. Shanghai Municipal Key Clinical Specialty [shslczdzk02503]

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Diabetes enhances kidney fibrosis by enhancing HIF-1 activation, leading to impaired kidney repair. In diabetic mice, unilateral ureteral obstruction induces more renal fibrosis, apoptosis, and interstitial macrophage infiltration. High glucose-conditioned renal tubular cells show higher expression of fibrosis marker protein under hypoxia, which is mediated by increased HIF-1α expression. Knockout of proximal tubule-specific HIF-1α attenuates fibrosis induced by UUO in diabetic mice kidneys.
Diabetes may prevent kidney repair and sensitize the kidney to fibrosis or scar formation. To test this possibility, we examined renal fibrosis induced by unilateral ureteral obstruction (UUO) in diabetic mouse models. Indeed, UUO induced significantly more renal fibrosis in both Akita and STZ-induced diabetic mice than in nondiabetic mice. The diabetic mice also had more apoptosis and interstitial macrophage infiltration during UUO. In vitro, hypoxia induced higher expression of the fibrosis marker protein fibronectin in high glucose-conditioned renal tubular cells than in normal glucose cells. Mechanistically, hypoxia induced significantly more hypoxia-inducible factor-1 alpha (HIF-1 alpha) in high glucose cells than in normal glucose cells. Inhibition of HIF-1 attenuated the expression of fibronectin induced by hypoxia in high-glucose cells. Consistently, UUO induced significantly higher HIF-1 alpha expression along with fibrosis in diabetic mice kidneys than in nondiabetic kidneys. The increased expression of fibrosis induced by UUO in diabetic mice was diminished in proximal tubule-HIF-1 alpha-knockout mice. Together, these results indicate that diabetes sensitizes kidney tissues and cells to fibrogenesis probably by enhancing HIF-1 activation.

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