Transcriptomic signature : a spatially resolved analysis of the nephron structures in chronic kidney disease

Chronic kidney disease (CKD) is a global health threat, affecting over 10% of the world population, including an estimated 37 million Americans. Importantly, glomerular diseases account for 70% of all the CKD. To date, no effective treatment for CKD exists, except that of dialysis or transplantation, which are associated with comorbidities, complications, and poor quality of life. Both of these treatment options present an enormous economic burden on the healthcare system, not to mention that transplantation is not even readily available due to a shortage of donor organs. Therefore, new breakthrough knowledge to generate more potent therapies for CKD is needed.

In the glomerulus, podocytes and endothelial cells together with the glomerular basement membrane form the glomerular filtration apparatus, and damage to any one of its components leads to kidney disease. Many different theories of disease progression have emerged over time, ranging from podocyte depletion hypothesis to recent evidence for metabolic dysfunction. However, none of these claims have been able to clearly elucidate the exact path of progression, which has ultimately resulted in failed attempts for treatment.

To better understand disease mechanisms and the integrated function of the glomerular and tubular cell types we applied spatial transcriptome analysis tools to investigate patterns of gene expression in kidney biopsies from healthy patient and patients affected with Alport syndrome (AS), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). Single glomeruli and tubular and interstitial regions were selected and served as areas of interest for the generation of the Whole Transcriptome Atlas.

Results showed distinct separation between tubular and glomerular regions both in healthy as well as in diseased kidneys. Transcripts typical of glomerular cells were highly enriched in the glomeruli and not in the tubules. Marked differences were observed between glomeruli from AS, FSGS, MN and healthy control samples. Measurable differences in gene expression were also evident between the different etiologies possibly highlighting the mechanistic differences amongst them.

In conclusion, this strategy enables us to answer unresolved questions about glomerular and tubular damage during CKD and repair mechanisms and will help in the development of new therapies to halt disease progression. The knowledge gained from these studies might be applicable to other forms of CKD.

Learning Objectives:

1. To understand the basic principles of special transcriptomics

2. To learn the basic principles for interpreting spatial transcriptomic data