(853.13) The Molecular Chaperone, GRP170, Protects Against Acute Kidney Injury and ER Stress in Mice

Poster Board Number: E96

Teresa Buck (University of Pittsburgh), Aidan Porter (University of Pittsburgh), Wily Ruiz (University of Pittsburgh), Dennis Clayton (University of Pittsburgh), Stephanie Mutchler (University of Pittsburgh), Evan Ray (University of Pittsburgh), Allison Marciszyn (University of Pittsburgh), Lubika NKashama (University of Pittsburgh), Arohan Subramanya (University of Pittsburgh), Sebastien Gingras (University of Pittsburgh), Thomas Kleyman (University of Pittsburgh, University of Pittsburgh, University of Pittsburgh), Gerard Apodaca (University of Pittsburgh), Linda Hendershot (St. Jude Childrens Research Hospital), Jeffrey Brodsky (University of Pittsburgh)

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.

Support or Funding Information

This work was supported by NIH grant R01 DK117126 (T.M.B.), NIH grant R35 GM131732 (J.L.B.), NIH grant RO1 DK119252 (A.R.S.), NIH grant KO8 DK110332 (E.C.R), NIH grant GM54068 (L.M.H), NIH grant R01 DK119183 (G.A.), an NIH training grant T32 K091202 (A.P.), and the Cores of the NIH O’Brien Pittsburgh Center for Kidney Research (P30DK079307).

This work was supported by NIH grant R01 DK117126 (T.M.B.), NIH grant R35 GM131732 (J.L.B.), NIH grant RO1 DK119252 (A.R.S.), NIH grant KO8 DK110332 (E.C.R), NIH grant GM54068 (L.M.H), NIH grant R01 DK119183 (G.A.), an NIH training grant T32 K091202 (A.P.), and the Cores of the NIH Oamp;rsquo;Brien Pittsburgh Center for Kidney Research (P30DK079307).