Urinary ER Chaperones - Biomarkers of Glomerular ER Stress

Certain glomerulopathies (GN) feature impaired protein homeostasis in the endoplasmic reticulum (ER) of podocytes. Protein misfolding causing ER stress activates the unfolded protein response (UPR), a protective signaling network. Mesencephalic astrocyte-derived neurotrophic factor (MANF) and ERdj3/DNAJB11 are ER chaperones that may be secreted from cells during the UPR. In rats with membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS), secretion of MANF or ERdj3 from podocytes into urine identified glomerular ER stress/UPR activation. We address the biomarker potential of MANF and ERdj3 in human MN and FSGS. Glomerular gene expression of MANF and ERdj3 was increased in human MN and FSGS. Urinary MANF and ERdj3 were increased in proteinuric MN and FSGS compared to MN and FSGS in remission (low proteinuria), as well as other GNs, polycystic kidney disease, hypertension and healthy controls. In individuals with proteinuric MN or FSGS, amounts of urinary MANF and ERdj3 correlated weakly with proteinuria; correlation of MANF with ERdj3 was moderate. Males represented ~60% of persons in each group. eGFR in proteinuric MN and FSGS was >40 ml/min/1.73 m2. In MN, there were no significant differences in urinary MANF and ERdj3 between anti-PLA2R positive and negative individuals. In conclusion, proteinuric MN and FSGS show increased glomerular expression of MANF and ERdj3. High urinary levels of these ER chaperones correlate only weakly with proteinuria. In these GNs, urinary ER chaperones are thus non-invasive biomarkers of glomerular/podocyte ER stress. Such biomarkers may eventually be useful in identifying patients for therapies targeting ER protein misfolding.