Diabetes and Diabetic Nephropathy (DN) were appropriately prominent topics at this year’s meeting. Thursday’s afternoon session, “Glomerular Endothelial Cell Injury in Diabetic Nephropathy” was an important reminder that endothelial injury plays a critical role in this disease. Outstanding lectures by Drs. Salmon on the endothelial glycocalyx (with beautiful images of this hard to visualize structure), Isermann on activated protein C, and Nakagawa on eNOS and glomerular injury, all served to illustrate the diverse approaches needed to elucidate the complex pathways of endothelial injury. The first talk, by Dr Quaggin, entitled “VEGF and Angiopoietin in DN” was a masterful summation of the field, and as it is a subject close to my heart, I will summarize her presentation. Here are her take-home points:
- Disruption of vascular signaling pathways plays a central role in diabetic complications, including and especially in the kidney.
- Two vascular growth factors, both members of the tyrosine kinase signaling pathway, VEGF and Angiopoietin-1 (Ang-1), play protective roles in the glomerulus.
- The Ang-1 receptor, Tie-2, may be an important target for therapeutic intervention.
What is the role of VEGF in diabetic glomerulosclerosis? There is now little doubt that VEGF expression is increased in early phases. Healthy mice exposed to high VEGF levels appear to develop a lesion similar to DN. Similarly, healthy mice where VEGF has been knocked out developed lesions similar to thrombotic microangiopathy. Diabetic mice with VEGF knockout are particularly sensitive and rapidly progress to end-stage disease. These findings do not suggest an easy therapeutic option for this pathway.
Angiopoietins 1 (the major agonistic ligand) and 2 (a competitive antagonist), share a common receptor, Tie-2, that is almost exclusively expressed by endothelial cells. Angiopoietin 1 and 2 are antagonizing, with Ang-1 (produced in podocytes) promoting vessel integrity, inhibiting vascular leakage and inflammatory gene expression. In contrast, Ang-2 (stored in Weibel-Palade bodies and acting in a paracrine/autocrine manner) binding abrogates protective Ang-1/Tie2 signaling, increases inflammation, and promotes endothelial leakage and detachment. Ang-1 administration improves the microvascular complication of diabetes, and Ang-2 has been shown to be upregulated in diabetes. Congenital Ang-1 knockout is fatal, as it is critically important for cardiovascular development. However, when loss of Ang-1 is delayed until maturity, the phenotype is surprisingly normal, as long as the vasculature is not stressed. When these animals where given diabetes, they were found to be hyper-susceptible and showed early and high mortality. In addition, they showed aggressive fibrosis in response to wounds (ear-punch).
One might therefore conclude that supplementing Ang-1 and/or inhibiting Ang-2 would be reasonable therapeutic interventions. Unfortunately, it is simplistic to think that Ang-1 is always “good” and Ang-2 is always “bad”. For example, when both ligands (Ang-1 and Ang-2) are knocked out following birth, the mice develop glaucoma/blindness and cystic kidneys, not a very attractive option.
What about directly targeting the Tie-2 receptor? An abstract [TH-PO321] from her group addresses this possibility. VE-PTP is a Tie-2 selective phosphatase, which negatively modulates Tie-2 signaling intensity. They tested whether augmentation of Tie-2 signaling by a VE-PTP inhibitor (AKB-9785, Aerpio) protects against DN. 17-week treatment improved the general status of the diabetic mice and preserved their mGFR. While the drug had no effect on glucose levels, there was evidence of preservation of circulating insulin levels. Treatment with either recombinant Ang-1 or AKB-9785 rapidly induced Tie-2 phosphorylation. Administration of AKB-9785 to Ang-1 knock out mice confirmed ligand-independent Tie-2 activation occurs in vivo. Further experimentation is needed to understand this effect in greater detail.
This talk, together with the others, was a reminder that understanding and then modulating the glomerular and renal endothelium is an essential component in our struggle against DN.
Post by Dr. Isaac Stillman, AJKD Blog Contributor and AJKD Kidney Biopsy Teaching Case Advisory Board member.
Check out all of AJKD Blog’s coverage of Kidney Week 2015!