Abstract
Molecular chaperones are responsible for maintaining cellular homeostasis, and one such chaperone, GRP170, is an endoplasmic reticulum (ER) resident that oversees both protein biogenesis and quality control. We previously discovered that GRP170 regulates the degradation and assembly of the epithelial sodium channel (ENaC), which reabsorbs sodium in the distal nephron and thereby regulates salt-water homeostasis and blood pressure. To define the role of GRP170 — and, more generally, molecular chaperones in kidney physiology — we developed an inducible, nephron-specific GRP170-KO mouse. Here, we show that GRP170 deficiency causes a dramatic phenotype: profound hypovolemia, hyperaldosteronemia, and dysregulation of ion homeostasis, all of which are associated with the loss of ENaC. Additionally, the GRP170-KO mouse exhibits hallmarks of acute kidney injury (AKI). We further demonstrate that the unfolded protein response (UPR) is activated in the GRP170-deficient mouse. Notably, the UPR is also activated in AKI when originating from various other etiologies, including ischemia, sepsis, glomerulonephritis, nephrotic syndrome, and transplant rejection. Our work establishes the central role of GRP170 in kidney homeostasis and directly links molecular chaperone function to kidney injury.
Authors
Aidan W. Porter, Diep N. Nguyen, Dennis R. Clayton, Wily G. Ruiz, Stephanie M. Mutchler, Evan C. Ray, Allison L. Marciszyn, Lubika J. Nkashama, Arohan R. Subramanya, Sebastien Gingras, Thomas R. Kleyman, Gerard Apodaca, Linda M. Hendershot, Jeffrey L. Brodsky, Teresa M. Buck
Figure 6
The loss of GRP170 results in widespread kidney tubule dilation and kidney damage.
