Focal segmental glomerulosclerosis (FSGS) is a hereditary kidney disease caused by injury or loss of specialized cells in the kidney filters called podocytes. There is no known cure for hereditary FSGS, and available therapies are not very effective and associated with major side effects. A recent paper in the Journal of the American Society of Nephrology, entitled The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes, investigated how genetic mutations can manifest into FSGS, and found evidence that the disease may be treatable by existing and new therapeutic agents.
According to senior author Rasheed Gbadegesin, MD, MBBS, professor of pediatrics and medicine, scientists at Duke University previously reported that anillin (ANLN) gene defects are associated with FSGS, but how these defects result in disease remained unclear. The current study shows that mutations causing loss of function of the ANLN gene result in abnormal podocyte function and disruption of kidney filters in zebrafish models.
Gentzon Hall, MD, PhD, an assistant professor of medicine, and Brandon Lane, PhD, post-doctoral scholar in the Division of Pediatric Nephrology, further commented that the study cell-based experiments showed that some of the abnormalities caused by defective ANLN could be reversed by compounds targeting a biochemical pathway in the body called the PI-3K/AKT/mTOR/Rac1 pathway. The study authors conclude that drugs targeting these pathways may be useful in the treatment of FSGS caused by defective ANLN, and possibly other types of FSGS.
In addition to Gbadegesin, Hall, and Lane, study authors include Kamal Khan, Igor Pediaditakis, Jianqiu Xiao, Guanghong Wu, Liming Wang, Maria E. Kovalik, Megan Chryst-Stangl, Erica E. Davis, and Robert F. Spurney.
This study was supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants 1K08DK111940-01 (to G.H.) and 5R01DK098135 (to R.A.G.) and the American Society of Nephrology/Amos Medical Faculty Development Program/Robert Wood Johnson Foundation. Study authors acknowledge support from the Animal Models Core (Core A) and Renal Genomics Core (Core B) of the Duke O'Brien Center for Kidney Research supported by NIH NIDDK grant P30DK096493. R.F.S. is supported by grant R01 DK087707 and Veterans Affairs Merit Review BX002984.