It’s not all about the holes

We tend to focus our thoughts on the cysts on ADPKD, the holes that replace normal kidney tissue. But the evidence is accumulating that progression to End Stage Renal Disease (ESRD) is closely related to the fibrosis that occurs in the tissues surrounding the cysts.

Tissue is a group of biological cells.

Fibrosis is scar tissue.

Instead of smoothly organised layers of the different types of cells, in fibrosis you have clumps of redundant cells and debris that fill up the space and tend to overwhelm normal renal function.

There has been considerable research into the role of fibrosis in chronic kidney disease. Fibrosis in ADPKD kidneys is similar but with some additional features. Identifying these differences may lead to new therapeutic targets.

The information in this post has mainly come from a paper published in October 2011 in a special edition of the journal “Biochemical et Biophysica Acta (BBA) – Molecular Basis of Disease”. It isn’t on my breakfast reading list but came to my attention while I was reading around the topic of growth factors in ADPKD – thats for another post.

The paper is written by Dr Jill Norman, a *Reader in nephrology at UCL. Her main research interests are the mechanisms underlying kidney fibrosis.
(* a “Reader” in the academic world is a “Professor without a Chair” – amusing images!)

The paper is aimed at cell biologists and my reading of it entailed ferreting for definitions of the more obscure scientific terms .

Starting with what we know already:    In ADPKD there are defects in the polycystin proteins in kidney tubule cells that lead to the growth of cysts filled with fluid. Polycystin proteins may have other roles and research in Zebra fish suggests that polycystins may directly regulate collagen production.

Collagen is a structural protein that fills up spaces between cells, a biological equivalent of cement between bricks. There are different types of collagen. The grouping of collagens and other structural proteins is called the “Extracellular matrix”, ECM.

So, in ADPKD, loss of polycystin function can result in over-production of collagen.

The extra cellular matrix in an polycystic kidney contains an excess of fibroblasts, the cells that produce collagen. Some of these fibroblasts are derived from changes in other cells that normally perform other functions such as lining the blood vessels alongside the tubules. As the fibroblasts produce an excess of collagen it accumulates around the cysts and contributes to the fibrosis.

Specific to polycystic kidneys are alterations in the types of collagen. For example one protein called “tenascin”, which forms a thin lining between tubules in normal kidneys, in ADPKD becomes concentrated in focal clumps closely associated with small cysts.

What starts of as a process of repair and regeneration becomes disorganised and the remodelling of the extra cellular matrix becomes a spiral process of damage.

There are numerous mechanisms involved in this fibrosis:

  • an imbalance of growth factors – up regulation of pro-fibrotic factors and down regulation of anti-fibrotic factors
  • increase in vasoconstrictors such as Angiotensin II (AII)
  • decrease in vasodilators such as Nitrous oxide (NO)
  • hypoxia results from damage to the smallest of blood vessels
  • influx of inflammatory cells
  • damage to the DNA and RNA of the cells that can affect the rate at which cells replicate and die (apoptosis)

Schematic for the proposed model of fibrosis in ADPKD (image from reference paper)

Research can sometimes generate conflicting results and because there is not an exact animal model for studying polycystic kidneys it can be hard to know which of these processes are relevant in human polycystic disease. The variability in results leads to the conclusion that it is the interplay between all of these substances and processes that produce the end result, not any single defect in itself. Whilst this might sound like a tangled knot of threads it also means that there will be several different approaches for therapeutic intervention.
Fibroblasts from human ADPKD kidneys have been examined and compared to normal kidney fibroblasts. It has been shown that the PKD fibroblasts respond more to certain growth factors – they proliferate more, migrate less and produce a stickier collagen. The PKD cystic changes in the epithelium are associated with local changes in adjacent fibroblasts. This suggests that the interactions between fibroblasts and epithelial cells are probably of particular importance in the progression of the disease. To date the approach to ADPKD has been according to the premise that if the epithelial abnormality is corrected then the fibrosis will be obviated. However, the fact that fibroblasts can effect epithelial changes then correcting the epithelial abnormality may not be sufficient to prevent the fibrosis.
This obviously leads to the question – can anti-fibrotic treatments help with polycystic kidneys?
The answer is not yet clear, but it is hopeful.


Norman J, (2011) Fibrosis and progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD)  Biochemical et Biophysica Acta (BBA) – Molecular Baiss of Disease. Vol 1812 Issue 10, October 2011. 


One response to “It’s not all about the holes

  1. Pingback: Truth comes out in wine. | ROUGHLY-KIDNEY-SHAPED·

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