Next Generation Sequencing identifies Cdh11 and Mrc1 as novel translational biomarkers of kidney fibrosis

Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD. Overall design: mRNA sequencing of mouse kidney before and at various time points (1,2,3,7 & 14 days) after intraperitoneal treatment with folic acid.

18

Craciun FL, Bijol V, Ajay AK, Rao P, Kumar RK, Hutchinson J, Hofmann O, Joshi N, Luyendyk JP, Kusebauch U, Moss CL, Srivastava A, Himmelfarb J, Waikar SS, Moritz RL, Vaidya VS