An endoplasmic reticulum resident molecular chaperone, GRP170, prevents stress-induced glomerular injury

Abstract

The glomerulus, a unique capillary network in the nephron, filters an entire blood volume approximately 300 times a day. Specialized epithelial cells known as podocytes form a critical component of the glomerular filtration barrier, and diseases linked to podocyte injury include minimal change disease, focal segmental glomerulosclerosis, and diabetic kidney disease. Because podocytes are terminally differentiated, their ability to respond to external stress is critical. The unfolded protein response (UPR), a cellular stress pathway, is associated with glomerular injury, although the role of the UPR in glomerular injury is undefined. The UPR is initially protective, leading to upregulation of molecular chaperones, a class of proteins that promote protein folding and are required to survive oxidative and ischemic injury. An unresolved UPR, however, leads to apoptosis. We previously found that one molecular chaperone, GRP170, provides protection against acute kidney injury since GRP170 depletion led to UPR induction and widespread kidney injury. Here we generated a new podocyte specific GRP170 knock out mouse (GRP170Pd-/-). Surprisingly, GRP170Pd-/- mice were born healthy, and podocyte development appeared normal. Within a month, however, the knockout mice exhibited profound glomerular injury manifesting as proteinuria, hypoalbuminemia, hyperlipidemia, and kidney injury. Concomitant with glomerular injury, we observed increased expression of the pro-apoptotic UPR target, CHOP, in podocytes. Together, our new model not only defines a protective role for GRP170 against glomerular injury but also provides a new model to test the therapeutic potential of small molecule UPR modulators to treat glomerular injury.