Role for IL-11 Signalling in Diabetic Nephropathy

Background: Diabetic nephropathy (DN) is a leading cause of kidney failure in the developed world. As current therapies do not directly target fibrosis and inflammation driving disease progression, novel treatment strategies are needed. We hypothesized that Interleukin-11 (IL11), a pro-fibrotic and pro-inflammatory cytokine, contributes to DN pathogenesis and blocking IL11 may offer therapeutic benefit. Methods: We examined the role of IL11 in a mouse model of human DN: Akita (Ins2+/C96Y, (A)) mice carrying a renin transgene (R) on a susceptible 129 strain background (129AR). 129AR mice received monthly IP injections of IL11-neutralizing antibody (anti-IL11) or IgG control (50 mg/kg) for 12 weeks. In parallel, we generated a new 129AR mouse strain homozygous for a null mutation in the Il11 receptor subunit alpha 1 gene (Il11ra1 KO). We assessed albuminuria, blood chemistries, kidney molecular markers, histopathology, and mortality, and performed single nuclear RNA sequencing (snRNA-seq). Results: Urinary IL11 levels were elevated in 129AR mice compared to wild-type controls (p<0.0002), with a positive correlation between urinary IL11 and albuminuria (r=0.79; p<0.0001). By 20 weeks of age, anti-IL11 therapy led to a ~30% reduction in albuminuria from baseline (P<0.0001), while levels worsened in IgG controls. Anti-IL11 also attenuated renal inflammation and tubular injury, evidenced by reduced expression of Il6, Il1b, Tnfa, Ccl2, Ccl5, Kim1, Ngal mRNAs (p<0.0001), and improved kidney fibrosis and tubular dilation. At the molecular level, anti-IL11 inhibited ERK and NFκB signaling and suppressed epithelial-to-mesenchymal transition. In 129AR Il11ra1 KOs, albuminuria was significantly reduced by ~50% in 8-week-old mice and remained at relatively low levels throughout the study, in contrast to the progressive increase observed in 129AR controls (p<0.0001). snRNA-seq data revealed general reduction in pro-inflammatory pathways including IFN-, TNF- and IL17-signaling in Il11ra1 KOs. Both anti-IL11-treated and Il11ra1 KO 129AR mice exhibited improved kidney structure, preserved podocyte numbers, increased survival, and modest but significant reduction in blood glucose. Conclusion: Inhibition of IL11 signaling in a robust DN model improves albuminuria and kidney injury, highlighting its key role in DN pathogenesis and supporting IL11 blockade as a potential therapeutic strategy. Funding: Government Support – Non-U.S.