C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes

Although C-reactive protein (CRP) has been implicated as a risk factor in diabetes, its pathogenic importance in diabetic kidney disease (DKD) remains unclear. The present study investigated the potential role of CRP in DKD. Diabetes was induced by streptozotocin in human CRP transgenic and wild-type mice for assessment of kidney injury at 24 weeks by real-time PCR, immunohistochemistry and western blot analysis. In vitro, the pathogenic effect of CRP was investigated using human kidney tubular epithelial cells cultured with high glucose and/or CRP. We found that CRP transgenic mice developed much more severe diabetic kidney injury than wild-type mice, as indicated by a significant increase in urinary albumin excretion and kidney injury molecule-1 abundance, enhanced infiltration of macrophages and T cells, and upregulation of pro-inflammatory cytokines (IL-1 beta, TNF alpha) and extracellular matrix (collagen I, III and IV). Enhanced renal inflammation and fibrosis in CRP transgenic mice was associated with upregulation of CRP receptor, CD32a, and over-activation of the TGF-beta/SMAD and nuclear factor kappa B signalling pathways. In vitro, CRP significantly upregulated pro-inflammatory cytokines (IL-1 beta, TNF alpha, monocyte chemoattractant protein-1 [MCP-1]) and pro-fibrotic growth factors (TGF-beta 1, connective tissue growth factor [CTGF]) via CD32a/64. CRP was induced by high glucose, which synergistically promoted high glucose-mediated renal inflammation and fibrosis. CRP is not only a biomarker, but also a mediator in DKD. Enhanced activation of TGF-beta/SMAD and nuclear factor kappa B signalling pathways may be the mechanisms by which CRP promotes renal inflammation and fibrosis under diabetic conditions.