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.
Highlights
The kidneys maintain salt and water homeostasis, reclaim nutrients, and eliminate waste
The resulting GRP170fl/fl mice were crossed to a Pax8-reverse tetracycline-dependent transactivator (rtTA)/LC-1 mouse to create triple-transgenic GRP170fl/fl/Pax8/LC-1 animals homozygous for the GRP170 floxed allele and containing at least one copy of the Pax8-rtTA (Pax8) and LC-1 alleles
The GRP170 knockout mouse exhibits initial signs of kidney failure Given the rise in plasma acute kidney injury (AKI) markers, evidence of proximal tubule dysfunction, and altered histology, we examined metabolic indicators of renal failure and chronic kidney disease (CKD)
Summary
The kidneys maintain salt and water homeostasis, reclaim nutrients, and eliminate waste. These critical functions are accomplished by ion channels and solute transporters expressed along the length of the nephron from the proximal tubule to the collecting duct. To respond to environmental changes, renal ion channels and transporters are subject to transcriptional and post-translational regulation. Posttranslational regulatory mechanisms govern protein folding, chemical modifications, protein trafficking through the secretory pathway, and degradation [1,2,3,4]. Each of these critical post-translational events is orchestrated by molecular chaperones. In contrast to our understanding of how molecular chaperones support these events, how members of this conserved protein family maintain organismal homeostasis and protein homeostasis (i.e., “proteostasis”) is understudied
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