Research News

Leslie Bruggeman, PhD, with co-investigators John Sedor, MD, and John O'Toole, MD, all members of the Department of Inflammation & Immunity, have been awarded a five-year, $2.8 million grant from the National Institutes of Health to investigate the genetics and biochemical mechanisms of apolipoprotein L1 (APOL1), an innate immune protein linked to chronic kidney disease (CKD).

Chronic kidney disease represents one of the largest health disparities in the United States among African Americans, who are four times more likely to develop kidney disease compared to European Americans. The majority of this increased risk for kidney disease is attributed to the high population frequency of variants in the APOL1 gene, found only in individuals of African ancestry.

APOL1: A high-risk genotype 

"Evidence has shown recessive inheritance of genetic variants in APOL1 predispose individuals to CKD. When individuals with an APOL1 high-risk genotype are then exposed to environmental triggers, such as viral infections, kidney disease typically develops," said Dr. Bruggeman, staff. "Our goal is to understand the mechanisms of CKD caused by APOL1 genetic variants and the role of the inducing environmental triggers to ultimately design targeted therapies either directed at the genetic risk or the environmental triggers. This new grant will help us to understand the difference between the APOL1 variants and why some cause CKD, whereas others do not."

In previous studies published in PLoS One the team found the non-disease or "normal" APOL1 variant (called APOL1-G0) expressed on podocytes, a type of kidney cell, may have a protective role against podocyte loss or injury when exposed to an environmental stressor.

Investigating innate immune responses and gene environment interactions

In the current study, the team will utilize HIV infection as an environmental trigger to investigate the function of the "normal" APOL1 variant in podocytes. Their goal is to understand why podocytes express APOL1, and the function of APOL1 in the context of viral infection.

The researchers will utilize in vitro and preclinical models of HIV infection and kidney biopsies from CKD patients to examine differences in the expression of APOL1 variants and the downstream effects on innate immune responses, such as interferon signaling.

This vital data, clarifying the significance of APOL1 to podocyte disease responses, will be critical to the development of future therapies targeting APOL1-associated CKD in African Americans. The study will also provide a better understanding of specific types of gene-environment interactions that could be used to develop tractable prevention and treatment strategies.