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 knockout 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.

All cell types must maintain homeostasis under periods of stress. To prevent the catastrophic effects of stress, all cell types also respond to stress by inducing protective pathways. Within the cell, the endoplasmic reticulum (ER) is exquisitely stress-sensitive, primarily because this organelle folds, post-translationally processes, and sorts one-third of the proteome. In the 1990s, a specialized ER stress response pathway was discovered, the unfolded protein response (UPR), which specifically protects the ER from damaged proteins and toxic chemicals. Not surprisingly, UPR-dependent responses are essential to maintain the function and viability of cells continuously exposed to stress, such as those in the kidney, which have high metabolic demands, produce myriad protein assemblies, continuously filter toxins, and synthesize ammonia. In this mini-review, we highlight recent papers that link ER stress and the UPR with acute kidney injury (AKI), a disease that arises in ~10% of all hospitalized individuals and nearly half of all people admitted to intensive care units. We conclude with a discussion of prospects for treating AKI with emerging drugs that improve ER function.

GRP170 is an Hsp70‐like, molecular chaperone localized to the endoplasmic reticulum (ER). Two separate functions have been described for GRP170. First, GRP170 acts as a nucleotide exchange factor (co‐chaperone) for the ER lumenal, Hsp70, BiP. Second, GRP170 possess “holdase” activity, and independently binds to aggregation prone regions of proteins to maintain solubility. We previously demonstrated that GRP170 regulates the quality control of the epithelial sodium channel, ENaC. ENaC is responsible for sodium reabsorption in the distal nephron and regulates salt/water homeostasis, and therefore, blood pressure. To better understand how GRP170 impacts kidney function we generated an inducible, nephron specific, GRP170 KO mouse. Loss of GRP170 results in rapid weight/volume loss, electrolyte imbalance and significantly elevated aldosterone levels. The GRP170 KO animals also demonstrate many of the hallmarks of acute kidney injury (AKI) including elevated plasma BUN and creatinine levels. Loss of GRP170 also results in induction of the unfolded protein response (UPR) as shown by upregulation of UPR targets by qPCR (sXbp1, BiP, CHOP and ATF4) and western blotting. We hypothesize that sustained induction of the UPR leads to kidney injury associated with our model, alternatively, misregulation of ion channel trafficking and volume loss may contribute to the pathogenic phenotype. To begin to understand how loss of an ER localized chaperone results in profound kidney injury we treated our GRP170 KO mice with the UPR inhibitor, TUDCA, or a high‐salt diet. Preliminary data suggest both UPR induction and electrolyte imbalance may contribute to kidney injury associated with loss of GRP170.

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