Investigators are getting more and more interested in Cathepsins and their role in health and disease. Atherosclerosis and diabetes are closely associated and both involve extensive degradation of the aortic elastin. Cathepsins are lysosomal cysteine proteases mainly of three types S, L and B. There are some data on cathepsins involvement in inflammation and mortality. Recently, in the Sept 2011 issue of JAMA, higher cathepsin S levels were associated with increased mortality risk in elderly. Studies have confirmed that elevated levels of cathepsin S has been associated with worsening diabetes, obesity and atherosclerosis in mice and human models. And guess what:- the activity of cathepsin S is regulated at the cellular level by and endogenous inhibitor none other than our friend- cystatin C.
What about the role of cathepsins in renal diseases. The table below from a recent JCI journal describes the different types of cathepsins and what their roles are in many diseases.
There is some data that cathepsin L might be involved in proteinuric renal disease.
Podocytes are unique cells with a complex cellular organization, consisting of a cell body, major processes, and foot processes . Cell biologic and mouse genetic studies revealed that many proteins regulate the plasticity of the podocyte actin cytoskeleton. The onset of proteinuria, induced by either LPS or puromycin aminonucleoside is associated with the induction of cathepsin L expression and activity in podocytes. There is an emerging concept that the onset of proteinuria represents a migratory event in podocyte foot processes that is associated by the activation of cathepsin L. Podocyte cathepsin L expression is increased in a variety of human proteinuric kidney diseases, ranging from minimal change disease (MCD) to diabetic nephropathy. Cathepsin L–mediated proteolysis plays a critical role in the development of various forms of proteinuria. Cathepsin L–mediated degradation of dynamin leads to proteinuria in mice. The notion that dynamin is required for proper podocyte structure and function is further supported by the observation that overexpression of dominant-negative dynamin leads to a loss of podocyte stress fibers in vitro and development of proteinuria in mice.
(image source:- http://www.jci.org/articles/view/42918)
So basically, cathepsins are becoming more and more important players in renal and other non renal diseases. What is interesting is that cystatin C, which is being billed as a renal function marker is an endogenous inhibitor of cathepsin S and an important regulator. So if someone is in renal failure, there is increased cystatin C, there will be increased inhibition of cathepsin S. Either that will increase the levels ( substrate) or decrease it base on how it binds. Hmm.. is it really cystatin C or is it cathepsin S or other cathepsins. Something to ponder and watch out for more work on this field.
Image source: Wikipedia.com
http://www.jci.org/articles/view/42918 ( currently freely available)