Effects of Stimulating and Inhibiting IL11 Pathway in Kidney Fibrosis

Background: IL11 has been widely implicated as a major downstream effector of TGFβ signaling driving fibrogenesis and extracellular matrix deposition in several organs including the kidney. Here, we aimed to test fibrotic effects of IL11 in in vitro and in vivo kidney disease models. Methods: Primary renal fibroblasts and human precision-cut kidney slices (PCKS) were treated with TGFβ in the absence or presence of anti-IL11 mAb or anti-TGFβ as positive control. Fibrotic gene expression and ECM accumulation were measured with qRT-PCR, ELISA and picrosirius red (PSR) staining. The in vivo effects of IL11 on fibrosis and kidney function were tested on 12-week old db/db-UNX mice subject to daily subcutaneous dosing of recombinant mouse IL11 for 8 weeks (10, 100, 200 ug/kg). The anti-fibrotic effects of anti-IL11 were assessed using unilateral ureteral obstruction (UUO) mice that were treated with single-dose anti-IL11 and anti-TGFβ mAb. Renal tissues were probed for fibrotic marker expression. Kidney function was assessed by serum creatinine, Blood Urea Nitro (BUN), and urine albumin-creatinine ratio (μACR). Results: In kidney fibroblasts and PCKS, TGFβ induced IL11, Fn1, Col4a1 and Col1a1. However, rhIL11 did not cause increase in fibrotic marker expression in these models. Furthermore, fibrotic marker expression and ECM accumulation were only partially inhibited by anti-IL11 in PCKS whereas no such effect was observed in primary kidney fibroblasts. Chronic administration of rmIL11 in db/db-UNX mice caused an increase in kidney weight, reduction in body weight and upregulated expression of FN, TIMP1 and Col1a1 genes, however no impact on renal function or accumulation of ECM was detectable in the IL11 treated mice. Both IL11 and TGFβ mAbs showed significant reduction in selective fibrotic markers compared to isotype control at Day 3 in UUO kidneys. Conclusions: We demonstrated that IL11 expression is induced by TGFβ. However, either IL11 by itself or its inhibition failed to significantly impact fibrosis in vitro or kidney function in vivo. Collectively, these data suggest that other factors in renal milieu play a more important role than IL11 to drive fibrosis in the kidney. Funding: Commercial Support - Janssen Pharmaceutical