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Kidney Week

Abstract: TH-PO907

Alk/bmp9 Signalization as a New Target of Therapy in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Author

  • Lora Gil, Cindy, Maisonneuve Rosemont Hospital, Montreal, Quebec, Canada
Background

Diabetic kidney disease one of the most frequent microvascular long-term complications in diabetic patients and is a major cause for the need of dialysis. Currently therapies in diabetic nephropathy are focusing on glycemia control and adequate arterial pressure levels in order to maintain an adequant glomerular filtration rate. However, a few of them are targeting the endothelial damage or podocyte-endothelial crosstalk, which play a critical role in diabetic kidney disease progression.
We have previously shown that Alk1, along with its ligand BMP9, plays an important function to maintain vascular integrity in diabetic animals. Loss of Alk1 signaling in diabetic animals led to dissociation of vascular junctions and increased vascular leakage. Given its role in the maintenance of endothelial quiescence and integrity, we evaluated the effects of Alk1 suppression on kidney integrity and renal function in diabetic mice.

Methods

We used mice with conditional deletion of Alk1 in the endothelium (Alk1ΔEC) to evaluate the role of Alk1 in glomerular filtration in STZ-induced diabetic mice. Mice were euthanized four months after the onset of diabetes and urine and serological analyzes were performed, along with immunohistochemical studies. Healthy patients biopsies were compared with patients already diagnosed with diabetic nephropaty

Results

We demonstrated that Alk1 haploinsufficiency worsens microalbuminuria and induces podocyte loss. Alk1 haploinsufficiency also increases extracellular matrix expression at the gromerular basement membrane.
Furthermore, a significant increase in glomerular apoptosis was observed in Alk1ΔEC mice. Analysis of homozygous Alk1ΔEC mice also revealed a significant loss of glomerular endothelial cells. Alk1 expression in the glomeruali was observed in patients diagnosed with diabetic nephropay compared to the healthy patients.

Conclusion

1.Partial loss of Alk1 in type I diabetic mice leads an increase in microalbuminuria compared to WT mice.
2.Heterozygous diabetic mice have an increase in apoptosis associated with podocyte loss.
3.Partial Loss of Alk1 in Diabetic mice Induces an increase in extracellular matrix synthesis.
4.The alk1 / bmp9 signaling could be a potential target of theraphy because it plays a critical role in the maintenance of glomerular endothelial cells and has an important functions to maintain glomerular integrity through a crosstalk podocyte-endothelial mechanism.

Funding

  • Clinical Revenue Support