Abstract: FR-PO193
Podocyte and Endothelial-Specific Elimination of BAMBI Identifies Differential TGF-β Pathways Contributing to Diabetic Glomerulopathy
Session Information
- Diabetic Kidney Disease: Basic - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Lai, Han, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Chen, Anqun, ZhongShan Hospital, Xiamen University, Xiamen, China
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Schlondorff, Detlef O., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
Transforming growth factor-β (TGF-β) is considered a central mediator of diabetic nephropathy (DN). The effect of TGF-β, mediated by type I TGF-β receptor, ALK5, and subsequent Smad2/3 activation is shown to result in podocyte apoptosis and loss. We previously demonstrated that the genetic deletion of BAMBI (BMP and Activin Membrane-Bound Inhibitor), a negative modulator TGF-β signaling, accelerates DN progression. Interestingly, worsening of DN phenotype in BAMBI-deficient mice was associated with heightened activation of ALK1 type I TGF-β receptor, whose expression is largely restricted to endothelial cells (ECs). ALK1 acts in an opposing manner to ALK5 in ECs via Smad1/5/8 activation, which results in EC activation, proliferation, and neo-angiogenesis.
Methods
Therefore, to evaluate the glomerular cell-specific effects of TGF-β in DN, we examined the effects of the podocyte- or EC-specific loss of Bambi in streptozotocin-induced diabetic mice with eNOS deficiency (eNOS-/-). Kidneys were examined at 20 weeks post diabetes induction.
Results
Interestingly, while hyperglycemia and body weight loss were similar in all groups of diabetic mice, significant hypertension was present only the diabetic mice with EC loss of BAMBI. Diabetic mice with podocyte- or EC-specific loss of BAMBI (Pod-Bambi-/- or EC-Bambi-/-) displayed markedly worsened albuminuria and DN severity in comparison to the control diabetic eNOS-/- mice. However, activation of Smad3 was further heightened in the glomeruli of diabetic Pod-Bambi-/- mice, whereas Smad1/5 activation was observed only in the glomeruli of diabetic EC-Bambi-/- mice. Consistent with the increased ALK1-Smad1/5-mediated angiogenesis in DN, significant EC proliferation was observed only in the glomeruli of diabetic EC-Bambi-/- mice.
Conclusion
These results identify cell type-specific TGF-β signaling in DN and further underscore the endothelial TGF-β signaling as a major contributor of diabetic glomerulopathy progression. Thus, attenuation of ALK1 and ALK5 signaling through BAMBI may be a potential therapeutic approach against DN progression.
Funding
- NIDDK Support