Abstract
Podocyte loss has been reported to relate to disease severity and progression in IgA nephropathy (IgAN). However, the underlying mechanism for its role in IgAN remain unclear. Recent evidence has shown that IgA1 complexes from patients with IgAN could activate mesangial cells to induce soluble mediator excretion, and further injure podocytes through mesangial-podocytic cross-talk. In the present study, we explored the underlying mechanism of mesangial cell-induced podocyte loss in IgAN. We found that IgA1 complexes from IgAN patients significantly up-regulated the expression of CXCL1 and TGF-β1 in mesangial cells compared with healthy controls. Significantly higher urinary levels of CXCL1 and TGF-β1 were also observed in patients with IgAN compared to healthy controls. Moreover, IgAN patients with higher urinary CXCL1 and TGF-β1 presented with severe clinical and pathological manifestations, including higher 24-hour urine protein excretion, lower eGFR and higher cresentic glomeruli proportion. Further in vitro experiments showed that increased podocyte death and reduced podocyte adhesion were induced by mesangial cell conditional medium from IgAN (IgAN-HMCM), as well as rhCXCL1 together with rhTGF-β1. In addition, the over-expression of CXCR2, the receptor for CXCL1, by podocytes was induced by IgAN-HMCM and rhTGF-β1, but not by rhCXCL1. Furthermore, the effect of increased podocyte death and reduced podocyte adhesion induced by IgAN-HMCM and rhCXCL1 and rhTGF-β1 was rescued partially by a blocking antibody against CXCR2. Moreover, we observed the expression of CXCR2 in urine exfoliated podocytes in IgAN patients. Our present study implied that IgA1 complexes from IgAN patients could up-regulate the secretion of CXCL1 and TGF-β1 in mesangial cells. Additionally, the synergistic effect of CXCL1 and TGF-β1 further induced podocyte death and adhesion dysfunction in podocytes via CXCR2. This might be a potential mechanism for podocyte loss observed in IgAN.
Highlights
Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis worldwide and one of the main causes of end stage renal disease (ESRD) [1,2]
Compared with mesangial cells with non-IgA1 treatment, multiple cytokines were detected in human mesangial cells (HMC) medium incubated with cIgA1 from IgAN patients or healthy controls, including MIF, Serpin E1, CXCL1, IL-6, IL-8, MCP-1, C5a, CD40L, CCL1, sICAM-1, IFN-γ, IL-23 and sTREM-1 (Figure 1A)
The expression of CXCL1 by mesangial cells was significantly upregulated in the IgAN-HMC group compared to the healthy controls (HC)-HMC group (718.4 ± 532.1 pg/ml vs. 311.6 ± 191.8 pg/ml, p = 0.002) (Figure 2A)
Summary
Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis worldwide and one of the main causes of end stage renal disease (ESRD) [1,2]. In recent years, emerging evidence has indicated the key role of circulating complexes that contain aberrant glycosylated IgA1 in driving their mesangial deposition and the triggering of glomerular injury in IgAN [7,8,9,10,11], even if the exact composition and physicochemical characteristics of the circulating complex remain unclear. The diagnostic histological features of IgAN are the deposition of pathogenic IgA1 complexes (cIgA1) in the glomerular mesangium [1,2], which indicates mesangial cell as the first target of injury. Injury to other renal intrinsic cells is observed in a considerable proportion of patients with IgAN. Several studies reported podocyte loss in the renal tissues of IgAN patients and further identified the predictive role of podocytopenia in IgAN progression [12,13,14]
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