Investigating Extracellular Vesicles as a Link Between Obesity and Chronic Kidney Disease

National Institute On Aging

Investigators

Abstract

here is a high burden of both chronic kidney disease (CKD) and obesity in the United States. As of 2023, approximately 35.5 million adults in the U.S. have CKD, with most CKD patients being 65 years or older. This burden is increasing due to a growing population of older individuals. Notably, both CKD and obesity rates are disparate between Black and White Americans. Black Americans have significantly higher incidence of CKD, higher rates of end-stage renal disease (ESRD), and the highest increase in mortality from CKD of any racial group in the United States. Similar disparities are observed in the burden of obesity. Approximately 41.9% of adults in the United States are obese with a higher prevalence in African Americans than White Americans. Studies have investigated the association of obesity with CKD. Obesity is a risk factor for CKD, and obese patients progress from kidney disease to ESRD faster than non-obese patients. In addition, the risk of ESRD increases in a directly proportionate manner to body mass index (BMI) categories. Obesity is also associated with more proteinuria and enlarged glomeruli which result in downstream health consequences such as renal insufficiency, hypertension, and obstructive sleep apnea. Multiple mechanisms have been proposed to explain the impact of obesity on kidney disease, however, there is a knowledge gap surrounding the mechanism by which obesity impacts CKD. This is especially important given the rise in obesity rates worldwide, with nearly one-third of the global population being overweight or obese. While it is known that obesity is a risk factor for CKD, we do not fully understand how obesity contributes to CKD. It is imperative to understand communication between tissues and organ systems to determine how obesity can lead to other comorbidities. Due to their role as intercellular communicators between cells and tissues, extracellular vesicles may be candidates for elucidating how obesity affects the pathophysiology of CKD. Extracellular vesicles (EVs) are membranous structures that are released into the extracellular environment, including into various biofluids, where they can be easily isolated. EVs encompass a wide range of particles including exosomes, microvesicles, and apoptotic bodies but are generally referred to as EVs due to commonalities in size and cargo among these particles. EVs have recently garnered attention due to their promising potential as biomarkers of a range of diseases and the minimally invasive nature of collecting EVs from biofluids. EVs also cargo bioactive cargo including proteins, lipids, and nucleic acids. Previously, we reported that EVs can carry circulating cell-free mitochondrial DNA (ccf-mtDNA) as cargo and that EV-associated ccf-mtDNA was present in higher concentrations in the plasma of frail individuals compared to non-frail individuals. Ccf-mtDNA can be released into the extracellular space and act as damage-associated molecular pattern (DAMP) molecule. DAMPs are released into the extracellular space upon cellular damage and provoke downstream pro-inflammatory effects. Emerging evidence indicates that EVs and their associated cargo may be important mediators of communication in obesity and in kidney disease. However, little is known about the role that EVs may play between CKD and obesity. In this proposal, we will investigate whether EVs and their associated cargo differ between obese individuals with and without CKD in a cohort of socioeconomically diverse African American and White adults from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Our study utilizes plasma EVs, which may lend insight to how circulating EVs impact CKD in the context of obesity. We aim to provide new insight into how EVs impact the development of CKD in obese individuals. In our cross-sectional analyses, we found significant interactions for EV mtDNA levels between race and CKD status, poverty status and CKD status, and sex and CKD status. EV mtDNA levels were significantly lower in participants within the African haplogroup who developed CKD compared to participants within the European haplogroup who developed CKD and the African haplogroup control group. In our longitudinal analyses individuals who developed CKD had lower EV mtDNA levels. Stratification by haplogroup showed that among participants within the African haplogroup, those who developed CKD had significantly lower EV mtDNA levels than those in the control group. In conclusion, EV mtDNA levels were lower in individuals who develop CKD. Our findings demonstrate that CKD status and mtDNA haplogroup influence EV cargo in obese individuals. This may provide targets for intervention in future studies.