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. We have pioneered the discovery of urinary ER stress biomarkers for early diagnosis and therapeutic intervention. One patent (US 10,156,564) was issued by the US Patent and Trademark Office in Dec. 2018, and another patent is pending.
1. Mesencephalic astrocyte–derived neurotrophic factor (MANF)
MANF localizes to the ER lumen and is secreted in response to ER stress in several cell types. By using mouse models of human nephrotic syndrome (NS) caused by mutant laminin ß2 protein–induced podocyte ER stress and acute kidney injury (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.
2. Cysteine-rich with EGF-like domains 2 (CRELD2)
CRELD2 is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress–induced NS and tunicamycin- or ischemia-reperfusion–induced AKI, respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery.
Our discovery of novel urinary ER stress biomarkers has potential utility in early diagnosis, risk stratification, monitoring treatment response, and directing ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology. We will continue to discover and validate more urinary ER stress biomarkers to stratify and treat kidney disease patients.