Information Clearinghouse, more than 20 million people inthe United States over the age of 20 suffer from chronic kidney disease. Thestudy, entitled "A systems approach identifies HIPK2 as a key regulator ofkidney fibrosis," was published in the March 11 issue of Nature Medicine.
The research was led by Dr. John Cijiang He, professor ofNephrology and Pharmacology and Systems Therapeutics, and Dr. Avi Ma'ayan, assistantprofessor of Pharmacology and Systems Therapeutics at Mount Sinai School ofMedicine, corresponding authors for the study. Three mouse models of kidneyfibrosis were studied, with one group containing HIV viral proteins integratedinto their genomes, another having been injected with a high dose of folic acidand a third in which kidney filtration was blocked in one kidney. All arefactors that lead to kidney fibrosis.
After the introduction of the different factors, the geneticmaterial of the mice was collected and compared to the genetic material of micenot afflicted with kidney fibrosis. Analysis was performed by theExpression2Kinases software, a computational systems biology algorithm andsoftware developed by the Ma'ayan Laboratory at Mount Sinai. Results showedthat HIPK2, a protein kinase (or regulator), was found to be highly active inmice with kidney fibrosis. When the kinase was eliminated, He and Ma'ayandiscovered that fibrosis became less prominent, and the condition of theaffected mice saw significant improvement.
Though He notes that little study has been done on HIPK2, thekinase is known to be responsible for regulating the expression of certaingenes and interacting with several signaling pathways related to kidneyfibrosis. In addition, it is believed that it might play a role in cancer.
"Based on our study, I think this kinase is very importantfor fibrosis, I think not only limited to kidney fibrosis, maybe also importantfor liver fibrosis or lung fibrosis," says He. "We believe that HIPK2—maybeit's a target for fibrosis treatment."
The current standards of care for dealing with kidneydisease are steroids and immunosuppression, but He notes that the non-specificdrugs come with side effects. There are currently no specific drugs availableto treat kidney fibrosis.
"This study is an important example of the translationalresearch we are doing at Mount Sinai," Ma'ayan said in a press release. "Usingalgorithms and software developed here, we worked with Dr. He, who is a kidneydisease physician and scientist, to better understand what causes kidneyfibrosis, and we are now one step closer to finding a therapeutic solution to acomplex disease that affects millions of Americans."
The systems approach offered by the Expression2Kinasessoftware allowed the researchers a new and more effective way of identifying atarget, as HIPK2 is a regulatory protein that is modified during chronicdisease. The researchers were not able to identify the high activity of theprotein kinase with normal methods of examining gene expression changes, butmodeling a network of proteins via computational systems biology allowed themto identify HIPK2.
"It's always difficult to find an effective drug target; thesignal network is so complex. If you block one, you don't know which is morepredominant compared to another one. So I think that the program that wedeveloped essentially helps us to screen more effectively," says He, addingthat the system allows them to examine the network as a whole to determinewhich pathways are more predominant.
He believes that HIPK2 should represent a fairly easy targetin 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 nuclearkinase, it's localized in the nuclei of cells, but the small molecule can easilyget into the cell or get into nuclei."
The next step for this research, he says, is to develop asmall-molecule inhibitor for HIPK2, as well as validating the animal model. Inaddition, he says Ma'ayan will be working to further improve the systems software.
"Our findings have important implications for people withkidney diseases, patients I treat every day," said He in a press release."Protein kinases like HIPK2 are highly effective therapeutic targets. We lookforward to exploring this further."
Funding for the study was provided by the National Instituteof Diabetes and Digestive and Kidney Diseases, a division of the NationalInstitutes of Health.
