Revisiting Glomerulopathy in Clusterin Knockout Mice: A Mouse Model of Human Immunotactoid Glomerulopathy

Clusterin (CLU) is a chaperone-like glycoprotein, and CLU knockout (KO) mice spontaneously develop age-dependent glomerulopathy with microtubule formation. However, its clinical relevance has not been confirmed yet. Immunotactoid glomerulopathy (ITG) is a clinicopathologic entity of glomerulonephritis characterised by glomerular deposits of electron dense microtubules. This study was to re-examine the glomerulopathy in CLU KO mice as compared with the pathological features of human ITG.

Kidney specimens from both wild type C57BL/6 (B6) and CLU-KO B6 mice were analyzed with haematoxylin and eosin, Masson-Trichrome, and Congo-red staining. IgG and DNAJB9 were detected by immunohistochemical staining, and the electron-dense mesangial deposits by transmission electron microscopy. Proteins were identified by liquid chromatography-mass spectrometry.

There were approximately 75% of glomeruli affected by moderate to severe mesangial lesions in 24-month-old male CLU-KO mice or 85% in 18-month-old female KO mice as compared with little or no glomerular pathology in WT mice at a similar age. The mesangial lesions were stained strongly positive with Masson-Trichrome-stained fibrosis, immunocomplex and anti-IgG, weakly positive with Congo-red, and negative with anti-DNAJB9 antibodies. The electron-dense material in the mesangium was structured with hollow microtubules with an average diameter of 50 nm. Functional enrichments with the STRING database revealed that secreted CLU-bound proteins mainly mediated complement activation and were associated with glomerulonephritis development.

Our data confirm that the glomerulopathy in CLU-KO B6 mice was similar to the pathological features of ITG and may therefore be considered as an experimental model of ITG. Further, CLU may negatively regulate the fibrillogenesis of ITG.