The research was led by Dr. John Cijiang He, professor of Nephrology and Pharmacology and Systems Therapeutics, and Dr. Avi Ma’ayan, assistant professor of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine, corresponding authors for the study. Three mouse models of kidney fibrosis were studied, with one group containing HIV viral proteins integrated into their genomes, another having been injected with a high dose of folic acid and a third in which kidney filtration was blocked in one kidney. All are factors that lead to kidney fibrosis.

 

After the introduction of the different factors, the genetic material of the mice was collected and compared to the genetic material of mice not afflicted with kidney fibrosis. Analysis was performed by the Expression2Kinases software, a computational systems biology algorithm and software developed by the Ma’ayan Laboratory at Mount Sinai. Results showed that HIPK2, a protein kinase (or regulator), was found to be highly active in mice with kidney fibrosis. When the kinase was eliminated, He and Ma’ayan discovered that fibrosis became less prominent, and the condition of the affected mice saw significant improvement.  

 

Though He notes that little study has been done on HIPK2, the kinase is known to be responsible for regulating the expression of certain genes and interacting with several signaling pathways related to kidney fibrosis. In addition, it is believed that it might play a role in cancer.  

 

“Based on our study, I think this kinase is very important for fibrosis, I think not only limited to kidney fibrosis, maybe also important for liver fibrosis or lung fibrosis,” says He. “We believe that HIPK2—maybe it’s a target for fibrosis treatment.”  

 

The current standards of care for dealing with kidney disease are steroids and immunosuppression, but He notes that the non-specific drugs come with side effects. There are currently no specific drugs available to treat kidney fibrosis.  

 

“This study is an important example of the translational research we are doing at Mount Sinai,” Ma’ayan said in a press release. “Using algorithms and software developed here, we worked with Dr. He, who is a kidney disease physician and scientist, to better understand what causes kidney fibrosis, and we are now one step closer to finding a therapeutic solution to a complex disease that affects millions of Americans.”

 

The systems approach offered by the Expression2Kinases software allowed the researchers a new and more effective way of identifying a target, as HIPK2 is a regulatory protein that is modified during chronic disease. The researchers were not able to identify the high activity of the protein kinase with normal methods of examining gene expression changes, but modeling a network of proteins via computational systems biology allowed them to identify HIPK2.  

 

“It’s always difficult to find an effective drug target; the signal network is so complex. If you block one, you don’t know which is more predominant compared to another one. So I think that the program that we developed essentially helps us to screen more effectively,” says He, adding that the system allows them to examine the network as a whole to determine which pathways are more predominant.

 

He believes that HIPK2 should represent a fairly easy target in terms of therapeutics.  

 

“It’s relatively easy to develop small-molecule inhibitors, and we’re actually in the process to do that,” He notes. “HIPK2 is a nuclear kinase, it’s localized in the nuclei of cells, but the small molecule can easily get into the cell or get into nuclei.”  

 

The next step for this research, he says, is to develop a small-molecule inhibitor for HIPK2, as well as validating the animal model. In addition, he says Ma’ayan will be working to further improve the systems software.  

 

“Our findings have important implications for people with kidney diseases, patients I treat every day,” said He in a press release. “Protein kinases like HIPK2 are highly effective therapeutic targets. We look forward to exploring this further.”  

 

Funding for the study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, a division of the National Institutes of Health.