Mesencephalic Astrocyte–Derived Neurotrophic Factor as a Urine Biomarker for Endoplasmic Reticulum Stress–Related Kidney Diseases

Abstract

Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin β2 protein-induced podocyte ER stress and AKI triggered by tunicamycin- or ischemia-reperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney disease

“…We and others have shown that it manifests as extensive tubular dilation, epithelial flattening, tubular basement membrane denudation, and loss of brush borders in proximal tubules, which peaks between 4 and 5 days after injection (21,29). In comparison, glomeruli and other organs are spared (21,29). We have also shown that, despite normal renal function and the absence of conspicuous histologic changes on day 1 after TM injection, multiple ER stress response genes including BiP, CHOP, MANF and ER degradation-enhancing α-mannosidase-like protein (EDEM) are upregulated (21).…”

“…In comparison, glomeruli and other organs are spared (21,29). We have also shown that, despite normal renal function and the absence of conspicuous histologic changes on day 1 after TM injection, multiple ER stress response genes including BiP, CHOP, MANF and ER degradation-enhancing α-mannosidase-like protein (EDEM) are upregulated (21). We further investigated whether CRELD2 was induced in ER-stressed renal tubules.…”

“…Tg-C321R mice begin to develop trace proteinuria by 4 weeks of age before any histological changes, then exhibit mild glomerulosclerosis, diffuse foot process effacement, GBM thickening, and overt proteinuria at approximately 6-8 weeks; they finally die after 10-12 weeks (5). At P24-P28, when Tg-C321R mutants exhibit trace proteinuria without notable renal histological alterations, podocyte ER stress induced by the C321R misfolded protein is evident as demonstrated by the upregulation of BiP and CHOP in Tg-C321R podocytes compared with WT and Tg-WT podocytes (5,21). In the current study, we expanded upon these findings by determining whether CRELD2 was also induced and secreted by ER-stressed podocytes at the early stage of proteinuria.…”

“…in mice is a well characterized AKI model caused by renal proximal tubular ER stress (29). We and others have shown that it manifests as extensive tubular dilation, epithelial flattening, tubular basement membrane denudation, and loss of brush borders in proximal tubules, which peaks between 4 and 5 days after injection (21,29). In comparison, glomeruli and other organs are spared (21,29).…”

High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver

“…MANF is an ER-localized protein that is secreted upon ER stress [33] and implicated as a marker and therapeutic of neurodegeneration [34–36]. Recently MANF’s potential as a disease biomarker has been investigated in both type I diabetes and kidney disease [37, 38]. Both found increased levels of MANF in serum and urine in disease-associated samples, respectively.…”