Endoplasmic Reticulum Stress Promotes the Development and Progression of Lupus Nephritis
Authors: Boesen Erika I. , Bonnemaison Mathilde L. 
Published: June 2021

Systemic lupus erythematosus (SLE) is an autoimmune disease predominantly affecting women. Endoplasmic reticulum (ER) stress has been associated with kidney disease, hypertension and inflammation, serious complications commonly observed in SLE patients. However, whether ER stress contributes to renal injury or hypertension in SLE is unknown. Accordingly, we performed two sets of studies in the NZBWF1 mouse model of SLE, testing whether blocking ER stress prevents the development of renal injury and hypertension, and whether blocking ER stress prevents further progression of renal injury after albuminuria develops.

In the prevention study, female NZBWF1 mice were treated from 20 weeks of age onwards with vehicle (drinking water) or a chemical chaperone to inhibit ER stress (sodium 4‐phenylbutyrate, 4‐PBA; 100 mM in drinking water; n=12/group). From 28 weeks, 24 h urine samples were collected weekly to monitor urine albumin excretion, with mice deemed albuminuric at 3+ or ≥300 mg/dL by dipstick measurement. The relative risk of 4‐PBA‐treated mice progressing to albuminuria before 36 weeks was 0.5 (95% confidence interval of 0.2–1.2, P=0.06 by Chi‐square test). At 36 weeks, anesthetized mean arterial blood pressure was measured (carotid artery cannulation), showing an approximate 16 mmHg reduction in 4‐PBA compared with vehicle‐treated mice (P=0.02, unpaired t‐test).

In the intervention study, mice were monitored for the onset of albuminuria as above, at which time mice were either sacrificed (onset group, n=6), or received vehicle (n=7) or 4‐PBA (n=7) for 4 weeks. Data were compared by one‐way ANOVA followed by post‐hoc test. At sacrifice, blood urea nitrogen was significantly reduced in 4‐PBA compared with vehicle‐treated mice (P<0.05) although plasma creatinine concentration was not significantly different between groups. The hematocrit of 4‐PBA‐treated mice was maintained at the same level as the onset group, whereas hematocrit of the vehicle group was significantly lower than both (P<0.05), suggesting plasma volume expansion. Left ventricle to body weight ratio was increased in the vehicle group compared with both 4‐PBA and onset groups (P<0.05), which were not different to each other. Renal histological analysis showed that vehicle‐treated mice had double the proportion of cortical tubules displaying dilation and approximately 5 times the proportion containing casts as compared with mice sacrificed at onset of albuminuria (P<0.05 for both), whereas 4‐PBA‐treated mice were not significantly different to onset mice. Glomerular injury and renal collagen deposition were significantly increased in vehicle‐treated mice compared to both the onset and 4‐PBA groups (P<0.05), which were not significantly different to each other.

Thus, treating NZBWF1 mice with 4‐PBA as a preventive measure delayed the development of albuminuria and blunted the development of hypertension in NZBWF1 mice. Commencing treatment with 4‐PBA once albuminuria had developed prevented the progression of glomerular and tubular injury. These data indicate that ER stress contributes to the development and progression of renal injury and hypertension in NZBWF1 mice, and suggest a therapeutic potential of ER stress inhibitors in ameliorating renal injury in SLE.

Support or Funding Information

Lupus Research Alliance (EIB) and American Heart Association (postdoctoral fellowship to MLB).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.