Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage

Abstract

Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein Tmem63c as a novel potential target. Tmem63c is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for tmem63c in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as Tmem63c for further translational investigation.

TMEM63C, a Potential Novel Target for Albuminuria Development, Is Regulated by MicroRNA-564 and Transforming Growth Factor beta in Human Renal Cells

“…Moreover, TMEM63C expression was found to be modulated by TGF-β stimulation in kidney cells. In addition to previous data [7], our data indicate that TMEM63C could be involved not only in GFB function but also in EMT.…”

“…Schulz et al [7] showed the importance of TMEM63C expression for the maintenance of GFB in zebra fish models and demonstrated its potential relevance in patients with focal segmental glomerulosclerosis in translational studies. However, until now, the expression regulation of TMEM63C is widely unexplored.…”

“…Schulz et al [7] showed a loss of TMEM63C expression in podocytes of patients with focal segmental glomerulosclerosis. In addition, functional studies in zebra fish models suggested that TMEM63C could play an important role in GFB function [7]. Nevertheless, the biological function of TMEM63C and its expression regulation are widely unknown.…”

“…Recently, a study identified transmembrane protein (TMEM) 63C as a novel candidate for albuminuria development [7]. TMEM63C, a member of the TMEM gene family, is expressed in the kidney, but also in many other tissues such as the cerebral cortex and endocrine tissues [7]. Schulz et al [7] showed a loss of TMEM63C expression in podocytes of patients with focal segmental glomerulosclerosis.…”

“…TMEM63C, a member of the TMEM gene family, is expressed in the kidney, but also in many other tissues such as the cerebral cortex and endocrine tissues [7]. Schulz et al [7] showed a loss of TMEM63C expression in podocytes of patients with focal segmental glomerulosclerosis. In addition, functional studies in zebra fish models suggested that TMEM63C could play an important role in GFB function [7].…”