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Abstract: SA-PO493

Decay Accelerating Factor (DAF), a Local Complement Inhibitor, Protects from Streptozotocin (STZ)-Induced Diabetic Nephropathy (DN)

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Cantarelli, Chiara, Icahn School of Medicine at Mount Sinai, New York, United States
  • Andrighetto, Sofia, Icahn School of Medicine at Mount Sinai, New York, United States
  • Hartzell, Susan, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Guglielmo, Chiara, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Fiaccadori, Enrico, Università di Parma, Parma, Italy
  • Zaza, Gianluigi, University of Verona, Verona, Italy
  • Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Glomerular deposition of complement components has been described in individuals with DN. Whether altered expression of DAF on podocytes mediates complement deposition in DN and affects disease severity is unknown.

Methods

We injected STZ (50 mg/kg, i.p.) into male WT and germline DAF-/- BALB/c mice and in B6 DAFfl/fl crossed to podocin Cre-transgenics (the B6 strain is resistant to STZ nephropathy). We serially measured urine albumin/creatinine ratio (ACR) and at 20 weeks we quantified histological injury and stained sections for C3b.

Results

STZ-induced nephropathy was associated with C3b deposition (Fig. 1A). In BALB/c mice, STZ caused more severe proteinuria in DAF-/- than in WT animals (Fig. 1B), a finding associated with more severe histological changes (Fig. 1C). Newly developed DAFfl/fl-podocin-CrePOS animals lacking DAF conditionally in podocytes showed albuminuria and histological changes of DN, while DAFfl/fl-podocin-CreNEG did not develop the disease (Fig. 1D-E). DAF-deficiency-induced proteinuria correlated with glomerular staining for C3b (Fig. 1E), mechanistically implicating DAF-dependent restraint on complement activation in the disease process.

Conclusion

Podocyte-expressed DAF mediates resistance to STZ-induced glomerular injury in B6 mice. In the absence of DAF, STZ-induced kidney injury is propagated by local deposition of complement. These data provide the rationale for further studies addressing a role for DAF/complement in human diabetic nephropathy.

Figure 1. A) C3b deposition in the glomeruli of BALB/c mice at 20 weeks after vehicle or STZ injection. B) Serial ACR in WT and DAF-/- BALB/c mice injected with STZ. C) H&E staining of kidney tissue of the same mice at 20 wks after STZ injection. D) Serial ACR in DAFfl/fl podocin-CreNEG and CrePOS WT B6 mice injected with STZ. E) Renal histology of the same mice at 20 wks after STZ injection. H&E (top) or C3b (bottom) staining. *P<0.05 vs. controls at the same time-point.

Funding

  • NIDDK Support