Molecular MR Imaging of Renal Fibrogenesis in Mice

Significance Statement BackgroundIn most CKDs, lysyl oxidase oxidation of collagen forms allysine side chains, which then form stable crosslinks. We hypothesized that MRI with the allysine-targeted probe Gd-oxyamine (OA) could be used to measure this process and noninvasively detect renal fibrosis.MethodsTwo mouse models were used: hereditary nephritis in Col4a3-deficient mice (Alport model) and a glomerulonephritis model, nephrotoxic nephritis (NTN). MRI measured the difference in kidney relaxation rate, & UDelta;R1, after intravenous Gd-OA administration. Renal tissue was collected for biochemical and histological analysis.Results & UDelta;R1 was increased in the renal cortex of NTN mice and in both the cortex and the medulla of Alport mice. Ex vivo tissue analyses showed increased collagen and Gd-OA levels in fibrotic renal tissues and a high correlation between tissue collagen and & UDelta;R1.ConclusionsMagnetic resonance imaging using Gd-OA is potentially a valuable tool for detecting and staging renal fibrogenesis. Renal fibrosis is the final common injury pathway for nearly all CKDs. Direct quantification of renal fibrosis would help to accurately assess disease progression and facilitate the development of novel antifibrotic therapies. We describe the feasibility of molecular imaging using a magnetic resonance (MR) probe, Gd-oxyamine (OA), in two mouse models of renal fibrosis (Alport syndrome and nephrotoxic nephritis). Quantitative, noninvasive MR imaging shows that the Gd-OA probe concentration increases in the renal tissues of diseased animals and that the imaging measure is proportional to the extent of tissue fibrosis assessed biochemically. Gd-OA molecular MR imaging is a potentially useful method to detect and stage renal fibrosis.

Automated summary

The study shows that magnetic resonance imaging combined with the Gd-OA probe can noninvasively detect and stage renal fibrosis, which is of great significance for accurately assessing disease progression and developing new antifibrotic therapies.