The PPAR-β/δ agonist GW0742 alleviates DNA damage and lupus nephritis in an animal model of systemic lupus erythematosus via restoring DNA repair gene expression

Abstract

Systemic lupus erythematosus (SLE) is a persistent autoimmune inflammatory disease associated with an elevated risk of kidney damage. The etiology of SLE remains unclear; nevertheless, current investigations increasingly indicate that increased DNA damage and deficiencies in the mechanisms of its repair might contribute to its pathogenesis, necessitating the identification and management of the disease. Therapies for SLE have improved considerably over recent decades. However, drugs that specifically address the underlying pathogenic pathways, such as potential DNA repair deficiencies, are unavailable. In this situation, drugs that ameliorate the altered DNA damage/repair might be a possible option for treating SLE. We investigated whether GW0742, an agonist of the peroxisome proliferator activator receptor β/δ, improves kidney function and ameliorates DNA damage/repair alteration in female lupus-prone mice. The results demonstrate that the repeated administration of GW0742 significantly ameliorates DNA damage/repair alteration in the bone marrow cells of lupus-prone animals, as assessed by the comet test. Furthermore, the administration of GW0742 restored the impaired DNA damage/repair pathway in lupus-prone mice by decreasing Gadd45a and p53 expression while elevating Ogg1 and Parp1 in the kidney tissues. The administration of GW0742 recovered the disturbed kidney redox balance in lupus-prone mice. It also ameliorated the altered biochemical markers related to lupus nephritis, as demonstrated by reduced levels of urinary protein and albumin, serum creatinine, and BUN. GW0742's protective outcome was verified by its ability to diminish the increased inflammatory marker MPO activity and ameliorated kidney histological characteristics of SLE. This suggests that GW0742 is a promising novel therapeutic agent for managing SLE and its associated complications.