Fibroblast Growth Factor 1 Ameliorates Diabetic Nephropathy Through an Anti‐inflammatory Mechanism

Abstract

A recent study demonstrated metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis (Nature. 2014; 513:436). But its strong mitogenic activity hampers its wide use in diabetes. We have recently engineered a FGF1 partial agonist carrying triple mutations (FGF1Δ HS) that diminish the ability of FGF1 to induce heparan sulfate (HS)‐assisted FGF receptor (FGFR) dimerization and activation. FGF1Δ HS exhibited a major loss in proliferative potential, while preserving the full metabolic activity of wild‐type FGF1 (FGF1WT). In the present study, we further tested the potential of FGF1Δ HS in treatment of diabetic nephropathy (DN). Treatment of db/db type 2 diabetes (T2D) with FGFWT and FGF1Δ HS (0.5 mg/kg) every other day for 2 months, both FGF1WT and FGF1Δ HS significantly reduced blood glucose, urinary albumin, and prevented glomerular hypertrophy, mesangial matrix expansion and renal fibrosis. Similarly, treatment of streptozotocin (STZ)‐induced type 1 diabetes (TID) with FGF1WT and FGF1Δ HS also significantly prevented diabetes‐induced renal morphological and functional changes, but without significant effects on blood glucose levels. These results imply that the renal protection of FGF1WT and FGF1Δ HS is independent of their insulin sensitizing activity. Since renal inflammation is a critical cause of DN, and FGF1 exhibits a potent anti‐inflammatory property (Nature. 2014; 513:436), we hypothesized that the protection of FGF1 against DN is associated with its anti‐inflammatory capability. As expected, both FGF1WTand FGF1 HStreatments significantly reduced the inflammatory cytokines (TNF‐α and IL‐6) expression and CD68+ macrophage infiltration in renal tissues in both T1D and T2D, which were accompanied by an inhibition of inflammatory signal (JNK/NF‐κB) activation. Direct exposure of renal mesangial cell to high glucose or TNF‐α induced similar inflammatory and fibrotic responses as observed in diabetes, which could be prevented by FGF1WTand FGF1Δ HSpre‐treatment. More importantly, administration of FGF1Δ HSto 9‐month‐old db/db mice completely prevented the further development of DN with remarkable amelioration of renal inflammation and fibrosis. These results demonstrate that FGF1 prevents DN largely via inhibiting renal inflammation. FGF1Δ HSmight be a therapeutic approach for the treatment of DN without promoting undesired tissue proliferation.