A Breakthrough in Kidney Fibrosis and Related Diseases

August 30, 2016

Kidney Fibrosis

Nearly 750 million people around the globe suffer from some form of chronic kidney disease (CKD). Caused primarily by high blood pressure or diabetes, CKD claims more than a million lives each year. Those who have the disease, including millions of children, require lifetime medical care that ranges from strict diets and medications to dialysis and transplants. There is no cure for the disease, but researchers may now be one step closer. 1

Pinpointing New Treatments

What do Twists, Snails, and CKD all have in common? For a team of research scientists based at the M.D. Anderson Cancer Center, University of Texas (UT), Austin, and Göttingen University Medical Center, Georg August University in Göttingen, Germany, understanding how to control two of the mechanisms that regulate EMT (epithelial mesenchymal transition) may provide the key to developing novel treatments for CKD as well as many other fibrosis-associated diseases, including cancer. 2   

EMT is a process whereby epithelial cells, which form the membranous tissue covering our internal organs and other internal surfaces of the body, morph into a variety of other cell types, including mesenchymal stem cells that become migratory and invasive. This process is known to occur in wound healing, the initiation of metastasis for cancer progression, and in organ fibrosis, including kidney fibrosis. In short, kidney, or renal, fibrosis is caused by the excessive accumulation of extracellular connective tissue resulting from kidney injuries and the organs’ inability to regenerate. This excessive tissue causes scarring and ultimately end-stage renal failure requiring dialysis, kidney transplantation, with potential fatal consequences. 3

What They Did

To investigate the impact of EMT on the development of CKD, the UT research team overexpressed or deleted both Snail and Twist genes in the tubular epithelial cells of specially bred mice. This enabled the scientists to prompt or suppress the EMT process to weigh its effect on the development of kidney fibrosis. Using Opal® Multicolor Immunohistochemistry (IHC) Research Kits, tissue from various downregulated and upregulated samples were stained and scanned using the Vectra® Automated Multispectral Imaging System. The instrument is considered among the most advanced and reliable tools for objective and high-throughput biomarker quantitation and colocalization study using multiplexed immunohistochemistry. 4 As the UT research progressed, five random fields per slide were selected for each mouse. YFP+ (yellow fluorescent protein) tubular cells were then scored and quantified based on the presence or absence of small integral membrane proteins, such as water channel proteins that are depleted during EMT, using inForm® Tissue Finder Software, which automates the detection and segmentation of specific tissue types using patented user-trainable algorithms developed to recognize morphological patterns. 5

From Mice To Men

Turning to biopsied renal tissue from humans, the UT researchers then probed the EMT-related genes in samples that exhibited renal fibrosis as well as normal kidney tissue. The results showed that protein levels of select tubular epithelial cells (TECs) were deregulated in those samples from fibrotic kidneys. Similar findings were discovered in the TEC cell line where there was evidence of a robust induction of EMT. While the researchers noted more research is needed, these initial results suggest that damaged kidneys could release an EMT program that further damages TECs. In fact, compromised kidneys may “result in a vicious cycle of damage and host response, leading to chronic fibrosis,” the researchers said. Equally important, the team’s research findings “support the notion of targeting the EMT program as a viable therapeutic strategy for protecting functional parenchyma in kidney fibrosis” in the future. 6

Not reported, but widely understood, is the fact that the UT research, methodology, and stunning cellular images generated by the PerkinElmer Vectra® Automated Multispectral Imaging System are equally applicable and significant to the ongoing study of EMT in all human organs, including cancer progression research– and that could well prove to be a huge leap forward in developing effective new treatments for all forms of fibrosis-based diseases.

The PerkinElmer instruments included in this article are for research use only.  Not for use in diagnostic procedures.

References

  1. Anon., “Chronic Kidney Disease,” World Kidney Day.
  2. Yossi Ovadya and Valery Krizhanovsky, “A New Twist In Kidney Fibrosis,” Nature Medicine, Vol. 21, pp. 975–977, 2015.
  3. Wilhelm Kriz, Brigitte Kaissling, and Michel Le Hir, “Epithelial-Mesenchymal Transition (EMT) In Kidney Fibrosis: Fact Or Fantasy?” The Journal of Clinical Investigation, February 1, 2011. See also Sara Lovisa, et. al. “Epithelial-To-Mesenchymal Transition Induces Cell Cycle Arrest And Parenchymal Damage In Renal Fibrosis,” Nature Medicine, Volume 21, pp. 998–1009, August 2015.
  4. Wei Huang, Kenneth Hennrick, Sally Drew, “A Colorful Future Of Quantitative Pathology: Validation Of Vectra Technology Using Chromogenic Multiplexed Immunohistochemistry And Prostate Tissue Microarrays,” Human Pathology, Volume 44, Issue 1, January 2013, pp. 29–38.
  5. Lovisa, et. al., op. cit.
  6. Ibid.

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