Sodium 4-phenylbutyrate treatment protects against renal injury in NZBWF1 mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease predominantly affecting women and often leading to lupus nephritis and kidney damage. Endoplasmic reticulum (ER) stress has been implicated in several forms of kidney disease, but whether ER stress contributes to renal injury in SLE is unknown. To investigate this, a small molecule chaperone, sodium 4-phenylbutyrate (4-PBA), was administered to the NZBWF1 mouse model of SLE. In a prevention study, treatment with 4-PBA from 20 weeks of age (prior to the development of renal injury) delayed the onset of albuminuria and significantly reduced additional indices of renal injury compared to vehicle-treated NZBWF1 mice at 36 weeks of age, including collagen deposition, tubular casts, renal cell apoptosis, and blood urea nitrogen concentration (BUN). To test whether ER stress contributes to the progression of renal injury once albuminuria has developed, mice were monitored for the onset of albuminuria (3+ or ≥300 mg/dL by dipstick measurement of 24 h urine sample) and once established, were either euthanized (onset group), or underwent 4-PBA or vehicle treatment for 4 weeks. Treatment with 4-PBA blocked the worsening of glomerular injury, reduced the number of dilated or cast-filled tubules and reduced the number of apoptotic cells compared to vehicle-treated mice. BUN and left ventricle to bodyweight ratio were also reduced by 4-PBA treatment. Renal expression of the endogenous chaperones, protein disulfide isomerase and GRP78, were increased in 4-PBA-treated mice. Together, these results suggest a therapeutic potential for agents like 4-PBA in combating renal injury in SLE.