Abstract: SA-PO382

Investigating Endoplasmic Reticulum Stress in the Development of Lupus Nephritis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Bonnemaison, Mathilde L, University of Nebraska Medical Center, Omaha, Nebraska, United States
  • Boesen, Erika I., University of Nebraska Medical Center, Omaha, Nebraska, United States
Background

Lupus nephritis is a common complication of the autoimmune disease systemic lupus erythematosus (SLE) and is associated with glomerular and tubular injury. Although albumin uptake has been shown to induce endoplasmic reticulum (ER) stress in proximal tubule cells in vitro, it is unknown whether ER stress occurs in and contributes to the development of renal injury in SLE.

Results

To investigate this, the current study used a well-established model of lupus nephritis, the NZBWF1 mouse (female only). Mice were randomized to receive either vehicle (normal drinking water) or the ER stress blocker 4-phenylbutyric acid (4-PBA, 20 mM) in drinking water starting from 12 weeks of age until 34 weeks of age or the onset of albuminuria, whichever came first. In a pilot study, this treatment protocol significantly reduced mRNA expression of the ER stress marker CHOP in both 20 and 34 week old NZBWF1 mice (Ptreatment=0.02). Mice were sacrificed at the onset of albuminuria (≥100mg/dL by dipstick) or at 34 weeks of age, whichever came first. The relative risk of the 4-PBA mice progressing to albuminuria before 34 weeks of age was 0.83 (95% confidence interval of 0.56-1.3, P=0.2 by Chi-square test). Blood urea nitrogen was significantly elevated in mice that developed albuminuria before 34 weeks of age (P<0.0001), but was not different between vehicle and 4-PBA groups. Plasma creatinine levels were unchanged over time in both groups. CHOP mRNA expression in the renal cortex was compared between untreated 20 week old mice (prior to SLE development) and vehicle-treated albuminuric and non-albuminuric 34 week old mice. Surprisingly, mRNA levels of the ER stress marker CHOP were significantly reduced in the renal cortex of albuminuric mice compared to the 20 week old mice (P<0.05), which had similar CHOP expression to 34 week old non-albuminuric mice. A similar trend was observed for GRP94, but this did not reach statistical significance.

Conclusion

Together, these findings do not support a major role for ER stress in the early stages of the development of renal injury in SLE, as defined by onset of albuminuria. Whether ER stress contributes to the further progression of renal injury in lupus nephritis once albuminuria has developed remains to be investigated.

Funding

  • Private Foundation Support