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Kidney Week

Abstract: PO0909

Integrin aVb8/TGF-b Activation in Kidney Is Associated with Renal Function Deterioration and Can Be Monitored in Urine

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wang, Xiaozhen, AstraZeneca, Gaithersburg, Maryland, United States
  • Conway, James, AstraZeneca, Gaithersburg, Maryland, United States
  • Kovacina, Kristina, Astrazeneca, South San Francisco, California, United States
  • Heasman, Stephanie C., AstraZeneca UK Ltd, Cambridge, Cambridgeshire, United Kingdom
  • Liarte Marin, Elena, AstraZeneca UK Ltd, Cambridge, Cambridgeshire, United Kingdom
  • Hess, Sonja, AstraZeneca, Gaithersburg, Maryland, United States
  • Boo, Chelsea, AstraZeneca, Gaithersburg, Maryland, United States
  • Feliers, Denis, AstraZeneca UK Ltd, Cambridge, Cambridgeshire, United Kingdom
  • Baker, David J., AstraZeneca UK Ltd, Cambridge, Cambridgeshire, United Kingdom
  • Sinsakul, Marvin V., AstraZeneca, Gaithersburg, Maryland, United States
  • MacPhee, Iain, AstraZeneca UK Ltd, Cambridge, Cambridgeshire, United Kingdom
  • Selvarajah, Viknesh, AstraZeneca UK Ltd, Cambridge, Cambridgeshire, United Kingdom
  • Moosmang, Sven M., AstraZeneca, Gothernburg, Sweden
  • Hsia, Judith, University of Colorado, Aurora, Colorado, United States
  • Hartleib-Geschwindner, Judith, AstraZeneca, Gothernburg, Sweden
Background

Integrin-TGFb activation plays a central role in fibrosis. The specificity of TGFb activation is regulated by the expression of integrin isoforms in tissues. We set out to study molecular signatures associated with various aetiologies in CKD, the specific integrins that modulate TGFb activation and fibrotic initiation in the kidney and the potential for non-invasive monitoring of renal TGFb activation.

Methods

Kidney biopsies were obtained from CKD cohorts of diverse aetiologies and living donor (LD) controls. Gene profiling data (Microarray) were obtained from glomeruli and tubulointerstitium. Renal integrin expression was evaluated and the correlation with TGFb activation as well as eGFR was assessed.

Results

In the Gene Set Variation analysis (GSVA), fibrosis signatures including collagen signature increased with CKD severity compared to LD. This was more prominent in diabetic nephropathy (DN) in both glomeruli (N=12, p=1.09e-04) and tubulointerstitium (N=17, 2.31e-04). Further analysis showed that renal integrin b8 (ITGB8) was enriched and elevated at CKD stage 2, maintained at the similar level at stage 3 and 4. ITGB8 was higher in DN tubolointerstitium (FC=1.23, p=5.56e-04, N=17) vs LD. Consistent with this, immune-histochemistry showed that ITGB8 protein was increased in tubular tissues in kidney biopsies from DN patients and co-localized with areas of fibrosis. Moreover, TGFb activation signature of 30 genes was significantly correlated with ITGB8 expression (R=0.58, p=2.39e-16, N=169) and inversely correlated with eGFR (p<0.01).
Active TGFb was detectable in urine by a Simoa immunoassay. The active TGFb/creatinine ratio was increased by 4.4 fold (p=0.0003) in CKD subjects (median: 7.5 ug/g, N=20) compared to non-CKD controls (1.4 ug/g, N=20). The level of active TGFb in urine can potentially identify patients at risk for fibrosis and progression of renal dysfunction.

Conclusion

In conclusion, fibrosis is associated with CKD severity, most prominent in DN. Integrin b8 is enriched in DN and correlates with TGFb activation. The fibrosis status may be monitored via measuring active TGFb in urine.

Funding

  • Commercial Support