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Abstract: FR-PO975

Loss of Glomerular Thrombomodulin Precedes Diabetic Nephropathy in Diabetic Patients

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Van Aanhold, Cleopatra Christina lioe, Leiden University Medical Center, Leiden, Netherlands
  • Bos, Manon, Leiden University Medical Center, Leiden, Netherlands
  • Bajema, Ingeborg M., Leiden University Medical Center, Leiden, Netherlands
  • Bruijn, Jan A., Leiden University Medical Center, Leiden, Netherlands
  • Baelde, Hans J., Leiden University Medical Center, Leiden, Netherlands
Background

Thrombomodulin (TM) is an endothelial transmembrane protein which regulates vascular homeostasis. Previously, it was demonstrated that TM-mediated protein C activation ameliorates glomerular apoptosis and inflammation in a DN mouse model (Nat Med 2007), indicating that diminished TM levels may contribute to DN. Cleavage of TM is a well-established feature of endothelial cell dysfunction, and serum levels of cleaved TM are increased in DN. Here, we investigate TM expression in glomeruli of patients with DN and in a DN mouse model.

Methods

We measured staining of glomerular TM in an autopsy cohort, including 94 DN patients, 57 diabetic patients without DN and 38 healthy controls. Additionally, TM mRNA expression was measured in microdissected glomeruli from renal biopsies of 24 patients with DN and 13 controls. Furthermore, we studied glomerular TM expression in a STZ-induced DN mouse model, including 20 STZ and 10 WT mice, at 5 and 15 weeks after diabetes induction – reflecting acute and chronic DN.

Results

TM expression was 1.7x lower in patients with diabetes compared to non-diabetic controls (p=0.004), but no differences were observed between diabetic patients with and without DN. TM mRNA levels of DN cases were 2.3x higher compared to control cases (p=0.017). In STZ mice, TM expression was 1.2x lower than in WT mice (p<0.001), but no difference in TM expression was observed between acute and chronic DN mice. TM expression correlated negatively with glomerular number of macrophages and TNF-α protein in these mice.

Conclusion

Glomerular TM expression is decreased on protein level, but increased on mRNA level in patients with DN. TM may be cleaved under diabetic conditions, which is compensated by increased production. Furthermore, a loss of TM is associated with increased glomerular inflammation in DN. Interestingly, no differences in TM levels were observed between diabetic patients with and without DN, nor between mice with acute and chronic DN. We speculate that TM loss is an early feature of the diabetic glomerulus, and contributes to glomerular inflammation and DN development. Restoration of TM levels may be a promising treatment to prevent DN in diabetic patients.