Complement classical and alternative pathway activation contributes to diabetic kidney disease progression: a...

Increasing evidence points toward an essential role for complement activation in the pathogenesis of diabetic kidney disease (DKD). However, the precise molecular mechanisms remain unclear, and the pathway predominantly contributing to complement activation in DKD is of particular interest. In this study, the glomerular proteome, especially the profiles of the complement proteins, was analyzed in kidney biopsies from 40 DKD patients and 10 normal controls using laser microdissection-assisted liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS). The glomerular abundances of three proteins related to classical pathway (CP) (C1q, C1r, C1s), five proteins related to alternative pathway (AP) (CFB, CFH, CFHR1, CFHR3, CFHR5), one common protein related to CP and lectin pathway (LP) (C4), and six proteins related to terminal complement pathway (C3, C5, C6, C7, C8, C9) were significantly increased in DKD. Notably, none of the proteins unique to the lectin complement pathway, including mannose-binding lectin (MBL) and its associated proteins, were detected in DKD glomeruli. Furthermore, the glomerular complement proteins of CP and AP were positively correlated with glomerular pathological grades and proteinuria, and negatively correlated with eGFR in DKD patients. Our results highlight a critical role for complement activation of the CP and AP, rather than the LP, in DKD progression.