The endoplasmic reticulum resident molecular chaperone, GRP170, is required to maintain podocyte homeostasis and function

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. One class of proteins, molecular chaperones, protects against cell stress by preventing protein misfolding, assisting in protein refolding, maintaining protein solubility, and modulating protein translation. We previously found that depletion of one such molecular chaperone, GRP170, in the renal tubule induces the unfolded stress response (UPR), a stress-responsive pathway originating in the endoplasmic reticulum (ER), and causes apoptosis and acute kidney injury in mice. Here we report on a new constitutive podocyte-specific GRP170 knockout mouse (GRP170 ^Pd-/- ). Surprisingly, GRP170 ^Pd-/- mice were born healthy. Within a month, however, these 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, and altered ER morphology in podocytes. Our new model not only defines a protective role for GRP170 against glomerular injury but provides a new avenue to test the therapeutic potential of small molecule UPR modulators to treat glomerular diseases.