Abstract
Proteinuria is an adverse prognostic feature in renal diseases. In proteinuric nephropathies, filtered proteins exert an injurious effect on the renal tubulointerstitium, resulting in inflammation and fibrosis. In the present study, we assessed to what extent complement activation via the lectin pathway may contribute to renal injury in response to proteinuria-related stress in proximal tubular cells. We used the well-established mouse model of protein overload proteinuria (POP) to assess the effect of lectin pathway inhibition on renal injury and fibrotic changes characteristic of proteinuric nephropathy. To this end, we compared experimental outcomes in wild type mice with MASP-2-deficient mice or wild type mice treated with MASP-2 inhibitor to block lectin pathway functional activity. Multiple markers of renal injury were assessed including renal function, proteinuria, macrophage infiltration, and cytokine release profiles. Both MASP-2-deficient and MASP-2 inhibitor-treated wild type mice exhibited renoprotection from proteinuria with significantly less tubulointerstitial injury when compared to isotype control antibody treated mice. This indicates that therapeutic targeting of MASP-2 in proteinuric nephropathies may offer a useful strategy in the clinical management of proteinuria associated pathologies in a variety of different underlying renal diseases.
Highlights
Proteinuria is a risk factor for the progressive decline of renal excretory function, and the development of renal fibrosis regardless of the primary renal disease [1,2,3,4,5]
To establish the role of the lectin pathway in renal TI inflammation, we studied the effect of MASP-2 gene ablation on experimental outcomes using the well-characterized model of protein overload proteinuria (POP)
The current studies using a wellestablished mouse model of proteinuria demonstrate that inhibiting the lectin pathway (LP) of complement activation by either genetic modification or pharmacologic intervention using specific antibodies blocking MASP-2 function leads to abrogation of renal injury without altering levels of experimentally induced proteinuria
Summary
Proteinuria is a risk factor for the progressive decline of renal excretory function, and the development of renal fibrosis regardless of the primary renal disease [1,2,3,4,5]. The concept of proteinuric nephropathy describes the toxic effects of excess protein entering the proximal tubule as a result of the impaired glomerular permeability [6, 7] This phenomenon, common to many glomerular diseases, results in a pro-inflammatory and pro-fibrotic environment in the kidney and is characterized by alterations in proximal tubular cell growth, apoptosis, gene transcription, and inflammatory cytokine production due to dysregulated signaling pathways stimulated by proteinuric tubular fluid. Complement activation has been widely described in immune complex-mediated and other glomerulonephritis, but several investigators have demonstrated an important role for complement in the development of tubulointerstitial (TI) fibrosis in non-glomerular disease [8,9,10] This may result from complement components filtered into the proximal tubule, abnormal synthesis of complement components by tubular cells or other resident or infiltrating cells, or altered expression of complement regulatory proteins by kidney cells [10, 11]. Given the paucity of new and existing treatments targeting inflammatory and pro-fibrotic pathways in renal disease, new avenues of therapeutic intervention deserve closer attention
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