Tumor Suppressor Protein p53 Affects Progression of Rare Kidney Disease

MedicalResearch.com Interview with:

Prof. Hirofumi Kai Kumamoto University Japan

Prof. Hirofumi Kai

Prof. Hirofumi Kai
Kumamoto University

MedicalResearch: What is the background for this study?

Dr. Kai: Alport Syndrome (AS) is a hereditary progressive kidney disease that affects 1 in 5000-10000 individuals in the US. Depending on the specific subtype and genetic mutation, the onset, symptoms and progression vary among patients. Some have earlier onset and severe phenotypes while others have slow progression towards end-stage renal disease (ESRD). The gene affected in Alport Syndrome is type 4 collagen, which codes for a protein component of the glomerular basement membrane (GBM). This mutation leads to the dysregulated proliferation (or dysplasia) of the GBM, which has an important role in urine filtration. The pathophysiological process of dysplasia indicates a dysfunction of protein/s that control cellular homeostasis. Because the tumor suppressor p53 is critically involved in modulating cell proliferation, we focused our attention on this protein.

MedicalResearch: What are the results of this study?

Dr. Kai: We found that in the mouse model of Alport Syndrome, p53 expression was down regulated compared with normal controls. To determine the involvement of p53 in AS progression, we established p53 knock-out AS mice. The severity of symptoms was clearer and the progression of Alport Syndrome was remarkably faster in p53-/- AS mice. The survival rate of p53-/- AS mice was much lower (15 weeks) than that of the p53+/+ AS mice (>21 weeks). These results suggested a protective role of p53 against the progression of AS. Specific deletion of p53 in the podocytes – cells that form slit diaphragm necessary for filtration – also resulted in more severe proteinuria. We also found by microarray analysis that in podocyte-specific p53-/- AS mice, many genes that are related to proliferation were up regulated, indicating a hyperplastic characteristic induced by the loss of p53.

MedicalResearch: What should clinicians take away from this report?

Dr. Kai: These findings provide critical information on the importance of p53 in modulating the proliferation of some renal cells, such as the podocytes. This study also highlights the need to define the main pathophysiological process that characterizes specific renal diseases. While some diseases such as diabetes nephropathy and acute kidney injury are characterized by renal cell apoptosis, other kidney diseases like Alport Syndrome, Minimal Change disease and glomerulosclerosis are distinguished by hyperproliferation. For those diseases that have hyperproliferative characteristics, p53 loss might be a critical factor for disease progression. On the other hand, rampant cell apoptosis indicates inappropriate activation of p53. To consider therapeutic approaches for kidney diseases, it is important to carefully evaluate the characteristic of the disease, whether it is hyperplastic or apoptotic. On the whole, our study adds significant information on how the severity and progression of Alport Syndrome (and possibly other similar kidney diseases) can be restrained, and opens up a new avenue for therapeutic approach.


Podocyte p53 Limits the Severity of Experimental Alport Syndrome

Ryosuke Fukuda, Mary Ann Suico, Yukari Kai, Kohei Omachi, Keishi Motomura,Tomoaki Koga, Yoshihiro Komohara, Kosuke Koyama, Tsubasa Yokota,Manabu Taura, Tsuyoshi Shuto, and Hirofumi Kai

JASN January 2016 27: 144-157; published ahead of print May 12, 2015, doi:10.1681/ASN.2014111109

Prof. Hirofumi Kai (2016). Tumor Suppressor Protein p53 Affects Progression of Rare Kidney Disease