Abstract: SA-PO310

Hypoxia-Induced Proteins as Novel Biomarkers of Early Stage Kidney Disease

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Ewart, Leah Mh, UCD Conway Institute, Dublin, Ireland
  • Creevey, Karen A, UCD Conway Institute, Dublin, Ireland
  • McEvoy, Caitriona M., UCD Conway Institute, Dublin, Ireland
  • Higgins, Debra F., UCD Conway Institute, Dublin, Ireland
Background

In the kidney, hypoxia (low oxygen) promotes fibrogenesis through stabilisation of hypoxia inducible transcription factors (HIFs), induction of pro-fibrogenic and pro-inflammatory gene expression, and modulation of the extracellular matrix. Inhibiting HIF-1 function attenuates renal fibrosis in vivo. As hypoxia is an early pathological feature of kidney injury, hypoxia-induced proteins may represent novel urinary biomarkers for detection of early stage renal injury.

Methods

Hypoxia-induced gene and protein expression was analysed in two pre-clinical models of kidney injury; reverse-unilateral ureteral obstruction (R-UUO) and gentamicin-sulphate-induced (GS) renal disease (40 or 120 mg/kg/day for 9 days), and in two independent kidney transplant biopsy collections from the GoCAR (Genomics of Chronic Allograft Nephropathy, United States) and the North Dublin Renal Biobank (Ireland) studies.

Results

A number of hypoxia-responsive genes were significantly increased in UUO and down-regulated with resolution of injury. Expression analysis of these genes revealed positive correlation with degree of injury and negative correlation with eGFR in the two independent renal transplant collections. Furthermore, urinary levels of the encoded hypoxia-responsive proteins correlated with injury in the gentamicin model and inhibition of their function protected the kidney from disease.

Conclusion

We conclude that hypoxia-responsive proteins are up-regulated during kidney injury, can be exploited as urinary biomarkers for early stage kidney disease and have potential as novel therapeutic targets for CKD.

Funding

  • Government Support - Non-U.S.