NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice

Area of Science:

• Nephrology
• Immunology
• Pharmacology

Background:

• Renal tubulointerstitial lesions (TILs) are key in chronic kidney disease (CKD) progression, marked by inflammation and fibrosis.
• Current treatments for TILs are largely ineffective, necessitating novel therapeutic strategies.
• Elevated IL-36α and NLRP3 inflammasome activation are implicated in CKD pathogenesis.

Purpose of the Study:

• To evaluate the therapeutic potential of NSC828779, a novel immunomodulatory salicylanilide derivative, for treating renal tubulointerstitial lesions.
• To investigate the mechanism of action of NSC828779 in inhibiting renal inflammation and fibrosis.

Main Methods:

• A mouse model of unilateral ureteral obstruction (UUO) was used to induce TILs.
• Renal tubular epithelial cells under mechanical stress were employed as an in vitro model.
• The effects of NSC828779 on renal pathology, inflammation markers, and fibrogenic signaling pathways were assessed.

Main Results:

• NSC828779 treatment significantly ameliorated renal lesions in UUO mice, reducing inflammation and fibrosis.
• The drug decreased urinary cytokine levels and specifically inhibited the IL-36α/NLRP3 inflammasome pathway.
• NSC828779 synergistically suppressed IL-36α-activated MAPK/NLRP3 inflammasome and STAT3/Smad2/3-dependent fibrogenic signaling.

Conclusions:

• NSC828779 demonstrates significant therapeutic efficacy against renal tubulointerstitial lesions.
• The compound acts by inhibiting the IL-36α/NLRP3 inflammasome and downstream fibrogenic pathways.
• NSC828779 represents a promising drug candidate for treating progressive renal inflammation and fibrosis in CKD.