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

Abstract

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 New Zealand Black x New Zealand White F1 hybrid (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 with vehicle-treated NZBWF1 mice at 36 weeks of age, including collagen deposition, tubular casts, renal cell apoptosis, and blood urea nitrogen (BUN) concentration. 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 killed (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 with vehicle-treated mice. BUN and left ventricle to bodyweight ratio (LV:BW) were also reduced by 4-PBA treatment. Renal expression of the endogenous chaperones, protein disulphide isomerase (PDI), and 78 kDa glucose-regulated protein (GRP78, also known as binding Ig protein (BiP)), 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.

The lupus susceptibility alleleDRB1*03:01encodes a disease-driving epitope

“…To determine whether the mitochondrial dysfunction observed in 65-79*LE-treated macrophages is secondary to ER stress, we used sodium 4-phenylbutyrate (4-PBA), a chemical chaperone that inhibits protein misfolding, thereby inhibiting ER stress 44 . Relevant to the present study, 4-PBA has been shown to prevent SLE manifestations in experimental lupus models 45,46 . As expected, 4-PBA inhibited 65-79*LE-activated ER stress and proteasomal degradation (Fig.…”

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

“…In a resiquimod-induced SLE mouse model, treatment with 4-PBA significantly mitigated ER stress signaling, attenuated splenomegaly—a common clinical manifestation in SLE -, reduced levels of TNF-α and anti-dsDNA, significantly ameliorated LN, reduced proportion of activated T and B lymphocytes and improved Treg-dependent immune suppression [ 39 ]. In another study involving a mouse model of SLE, treatment with 4-PBA increased renal expression of GRP78 and also mitigated renal injury development and progression [ 40 ]. These findings implicate noxious protein accumulation as a central component in the pathogenesis of SLE.…”

MicroR-380-3p Reduces Sepsis-Induced Acute Kidney Injury via Regulating RAB1P to Restrain NF-<i>κ</i>B Pathway

“…In GSE94717, the concentration of microR-380-3p is up-regulated in patients with septic AKI through analysis by GEO2R program. As an autoimmune disease, systemic lupus erythematosus is a reason for kidney injury (Bonnemaison et al 2019). In lupus nephritis patients with systemic lupus erythematosus, the concentration of microR-380-3p is increased and its increased levels may serve as a risk predictor in diagnosing patients with systemic lupus erythematosus companies with renal injury (Navarro-Quiroz et al 2016).…”