Zebrafish Model for Investigating Obesity-Related Glomerulomegaly (ORG)

by Assistant Professor Chalermchai Mitrpant, MD, PhD, Department of Biochemistry

Obesity-related glomerulomegaly (ORG) is a condition characterized by the following histopathological features:

  1. Enlargement of the glomerulus.
  2. Widening of the mesangial matrix, an increase in mesangial cell number, and dilation of capillaries.
  3. Hypertrophy of podocytes, the glomerular filtration cells.

ORG, a silent pathological condition, is observed in approximately 0.2% of individuals with obesity. Over the past two decades, the global increase in obesity due to dietary and lifestyle changes has led to a significant rise in ORG prevalence. This condition typically remains asymptomatic for years until kidney function declines, potentially progressing to chronic kidney disease (CKD) or end-stage renal failure. Among CKD patients, 15–30% also present with ORG.

The zebrafish (Danio rerio), a vertebrate with genetic and physiological similarities to humans, has been widely employed in biomedical research. In this study, we developed a diet-induced obesity (DIO) zebrafish model to investigate ORG. Histopathological analysis of zebrafish kidney tissues revealed glomerular enlargement consistent with ORG in humans. Additionally, changes in proximal tubule cells and focal segmental glomerulosclerosis (FSGS) were observed.

Gene expression profiling of kidney tissues from experimental zebrafish showed upregulation of genes associated with inflammation, fibrosis, and lipid metabolism. These findings suggest that this model is a valuable tool for elucidating the molecular mechanisms underlying ORG.

Future research can leverage advanced technologies, such as DESI-Imaging Mass Spectrometry (DESI-IMS), to analyze the spatial distribution of small biomolecules, including lipids, within affected tissues. Moreover, epigenomic approaches combining diverse omics datasets—such as ATAC-sequencing for chromatin accessibility analysis, histone modification profiling, and RNA sequencing—can provide insights into the regulatory networks governing gene expression in diseased versus healthy kidney tissues.

Comprehending the pathophysiological mechanisms of ORG will pave the way for preventive strategies and innovative therapeutic approaches in kidney disease management.