期刊
JCI INSIGHT
卷 7, 期 5, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.151869
关键词
-
资金
- NIH [T32 K091202, R01 DK117126, R35 GM131732, RO1 DK119252, KO8 DK110332, GM54068, R01 DK119183]
- Cores of the NIH O'Brien Pittsburgh Center for Kidney Research [P30DK079307]
Molecular chaperones, such as GRP170, play a crucial role in maintaining cellular homeostasis and kidney physiology. Deficiency of GRP170 causes hypovolemia, hyperaldosteronemia, ion homeostasis dysregulation, loss of epithelial sodium channel (ENaC), and exhibits signs of acute kidney injury. Furthermore, GRP170 deficiency activates the unfolded protein response (UPR), which is also seen in various other causes of acute kidney injury.
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.
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