Insights into cell growth, cell death offer new pathways to treat kidney disease
One of the challenges for kidney specialists is protecting the kidney from too much protein, which can contribute to progressive damage that leads to end-stage renal disease. Proximal tubule epithelial cells internalize albumin by receptor-mediated endocytosis and undergo apoptosis − programmed cell death − when exposed to too much albumin, the primary protein in the filtrate.
A team led by Elif Erkan, MD, MS, in the Division of Nephrology, has identified an interaction between receptors and proteins in the proximal tubule that support albumin endocytosis and cell survival. The link involves protein kinase B (Akt), a pivotal protein involved in cell survival, megalin-cubilin complex receptor and the endocytic adaptor disabled-2 (Dab2). Detailed findings appeared online Sept. 24, 2014 in the American Journal of Renal Physiology.
Specifically, Erkan’s team found that both Akt1 and Akt2 are involved in mediating albumin endocytosis in proximal tubule epithelial cells, and that Akt phosphorylates Dab2. In Akt1 and Akt2 knock-out mice, the location of Dab2 is shifted from the cell membrane to the perinuclear area of the proximal tubule indicating the role of Akt in trafficking of Dab2.
Erkan says the highlight of the work is the discovery of the link between the endocytic pathway and cell survival/cell death. “Because Akt mediates albumin endocytosis, its expression is down-regulated in tubular epithelial cells in kidney disease, leading to apoptosis” she says. “If we can figure out a way to up-regulate Akt in tubular epithelial cells, perhaps we can promote cell survival and prevent progression in glomerular diseases.”
Erkan and her team are continuing to study the link between Akt and Dab2 in mice. Additional research may identify other potential targets or additional regulating roles for Akt in a search for novel pharmaceutical agents to reduce kidney damage.
