Kidney Week

Abstract: FR-PO177

Excess Dietary Sodium Partially Corrects Salt and Water Homeostasis Caused by Loss of the Endoplasmic Reticulum Molecular Chaperone, GRP170, in the Mouse Nephron

Session Information

• AKI: Mechanisms
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Porter, Aidan W., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States

Aidan W. Porter, MD

• Vorndran, Hannah Elizabeth, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Hannah Elizabeth Vorndran

• Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Allison L. Marciszyn, PhD

• Mutchler, Stephanie, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Stephanie Mutchler

• Subramanya, Arohan R., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States

Arohan R. Subramanya, MD, FASN

• Kleyman, Thomas R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Thomas R. Kleyman, MD

• Brodsky, Jeffrey L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Jeffrey L. Brodsky, PhD

• Buck, Teresa M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Teresa M. Buck, PhD

Background

Correct folding and trafficking of ion channels and transporters by renal tubular epithelial cells is essential to maintain fluid and electrolyte homeostasis. These processes rely on proteins termed molecular chaperones to sustain protein biogenesis and coordinate the repair and recycling of misfolded proteins. We previously found that conditional loss of one such HSP70-like chaperone, GRP170, which resides in the endoplasmic reticulum (ER) of murine tubular epithelial cells leads to hypovolemia, electrolyte imbalance, and an AKI-like phenotype evidenced by tubular injury and elevated kidney injury markers. GRP170 deletion also compromises protein homeostasis and activates an ER quality control mechanism known as the Unfolded Protein Response (UPR). Based on these data, we hypothesized that UPR induction underlies hyponatremia, volume depletion, and AKI in rodents, but that these features might be rectified by intervention to maintain intravascular volume and, hence, renal perfusion.

Methods

Male and female inducible, nephron-specific GRP170 knockout (KO) mice were fed a control or an 8% sodium chloride diet. Serum and urine chemistries and concentration were measured. AKI markers and UPR induction was monitored by qPCR, western blot, and imaging. Renal histology and ER morphology were also assessed.

Results

Sodium supplementation improved electrolyte balance, intravascular volume, and AKI markers but failed to prevent weight loss or restore tubule integrity and function in GRP170 KO mice. UPR induction and ER morphology were also unaffected by excess sodium. Compared to males, female mice had milder kidney dysfunction, which was better ameliorated by sodium. However, GRP170 deletion produced a unique, sodium-independent UPR profile in both sexes.

Conclusion

An aberrant UPR contributes to kidney dysfunction in an inducible nephron-specific GR170 knockout mouse model. Moreover, GRP170 expression in the murine tubule is indispensable for protein homeostasis, cell integrity, and electrolyte balance. The distinct sex-specific phenotypes also indicate that the UPR may contribute to the relative susceptibility of each sex to kidney injury, highlighting the need to account for sex in AKI studies.

Funding

• NIDDK Support