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

The human kidneys filter the entire volume of the blood about 300 times each day. This ability depends on specialized cells, known as podocytes, which wrap around some of the blood vessels in the kidney. These cells control which molecules leave the blood based on their size. Normally large molecules like proteins are blocked, while smaller molecules including waste products, toxins, excess water and salts pass through into the urine. If this filtration system is damaged, by high blood pressure, for example, it can lead to chronic kidney disease. A hallmark of this disease, often called CKD for short, is high levels of the protein albumin in the urine. Previous studies involving rats with high blood pressure have found several regions of the genome that contribute to high levels of albumin in the urine, including one on chromosome 6. However, this region contains several genes and it was unclear which genes affected the condition. Schulz et al. set out to narrow down the list and find specific genes that might contribute to elevated albumin in the urine of rats with high blood pressure. This search identified the gene for a protein called TMEM63c as a likely candidate. This protein spans the outer membrane of podocyte cells. Analysis of kidney biopsies showed that patients with chronic kidney disease also had low levels of this protein in their podocytes. Further experiments, this time in zebrafish, showed that reducing the activity of the gene for tmem63c led to damaged podocytes and a leakier filter in the kidneys. The results suggest that this gene plays an important role in the integrity of the kidneys filtration barrier. It is possible that faulty versions of this gene are behind some cases of chronic kidney disease. If this proves to be the case, a better understanding of the role of this gene may lead to new treatments for the condition.