In the eye, glaucoma can lead to increased intraocular pressure and eventually permanent vision loss. Medicines used to treat this condition are usually diuretics and belong to a group of chemicals known as osmotic agents.
By dispersing into the bloodstream, they expose the cavities of our body to excessive pressure, drawing fluid out and reducing the pressure. This includes mannitol, a common chemical that is injected into a vein to address excess pressure in both the eyes and brain. However, this life-saving treatment is known to have a number of side effects, including the potential for acute kidney failure. Why this happens has continued to baffle researchers.
Now, a research team led by Associate Professor Naoya Sakamoto of Tokyo Metropolitan University has discovered an important part of the mechanism by which this could happen. Using mouse kidney cells, they applied the mannitol treatment and studied how it affected epithelial (skin or surface) cells in the proximal tubules, the part of the kidney that is thought to be vulnerable. most commonly treated with osmolyte. First, they confirmed that a transformation known as epithelial-mesenchymal transition (EMT) had occurred, effectively transforming the cells back to their original state, where they no longer functioned as normal cells. skin cells.
For example, they stop expressing E-cadherin, an important protein that helps hold cells together. EMT is strongly associated with kidney damage. Curiously, however, the same change was not seen for another osmolyte, urea. The team found that mannitol, which cannot pass through the membranes of these cells, causes the cells to contract on their own due to osmotic pressure, and it is this contraction that causes the problem.
Looking deeper into the structure of the cell, they found that the structure of the cell’s skeleton, the cytoskeleton, was significantly affected. The cytoskeleton is a network of tiny filaments made of the protein actin, and contains important aggregates called focal adhesions that help transmit mechanical stresses and stimuli from the outside of the cell to the inside. .
These concentrated binders were found to be rearranged in the presence of mannitol, accompanied by a significant increase in the incorporation of a specific type of actin called alpha-SMA into the filaments. The team went on to introduce an inhibitor that prevents the rearrangement of focal adhesions. It was shown that this step successfully prevented these changes in the cytoskeleton, and also prevented EMT from occurring with mannitol in the medium.
The team’s findings suggest that focal adhesion rearrangements play an important role in EMT in proximal tubular cells and suggest a strategy to block it. Translated into a therapeutic approach, this could lead to an enhancement of the therapeutic value of common osmotic agents as a life-saving treatment.
This work was supported by the Foundation for Scientific Research of MEXT, Japan (KAKENHI Grant Numbers 17H0277, 18H03521 and 18K19934).