Early Proinflammatory Activation of Renal Tubular Cells by Normal and Pathologic IgG

Abstract

Background/Aims: To verify whether human IgG induces proinflammatory activation of human proximal tubular epithelial cells (PTEC) independent of the metabolic overload of protein reabsorption. Methods: Cultured PTEC were incubated with normal IgG, IgG from systemic lupus erythematosus (SLE) patients, albumin or transferrin. IL-6 secretion and extracellular regulated kinase (ERK) activation (dual-phosphorylated ERK) were measured by ELISA and by Western blotting of PTEC extracts, respectively; renal biopsy specimens from patients with IgG and non-IgG proteinuria were analyzed by immunohistochemistry and in situ hybridization to detect ERK-P and IL-6. Results: Normal and SLE IgG, but not albumin or transferrin, induced an early significant increase in IL-6 secretion by PTECs. Also ERK activation was found after 1-hour incubation of PTEC with IgG, but not with control medium and albumin-treated PTEC. Activated ERK and IL-6 were found to colocalize in tubular cells in the kidney specimens of patients with IgG proteinuria only. Conclusion: IgG-dependent early activation of ERK and increased IL-6 secretion in PTEC suggest that IgG filtered during nonselective proteinuria may play a specific role in tubulointerstitial disease. Such a role could be particularly relevant in diseases associated with abnormal IgG pool compositions, such as SLE. Preliminary results on human renal biopsy specimens suggest that our in vitro observations may also be relevant in vivo.

Autoantibodies and Resident Renal Cells in the Pathogenesis of Lupus Nephritis: Getting to Know the Unknown

“…Mediators secreted by mesangial cells and HK-2 cells upon stimulation with anti-dsDNA antibodies can induce IL-6 secretion in the other cell types, indicating that there could be bidirectional communication or crosstalk between the glomerulus and tubulo-interstitium [5]. Consistent with our findings, Ronda et al also observed that immunoglobulins isolated from the sera of patients with SLE could induce IL-6 secretion in proximal renal tubular epithelial cells, and this was accompanied by the activation of the ERK signaling pathway [142]. …”

Mediators of Inflammation and Their Effect on Resident Renal Cells: Implications in Lupus Nephritis

“…Furthermore, at an identical anti-dsDNA IgG concentration, HK-2 cells demonstrated a more prominent induction of IL-6 secretion compared to mesangial cells, thereby highlighting the importance of proximal renal tubular epithelial cells in the immunopathogenesis of lupus nephritis [33]. Consistent with our findings, immunoglobulins of the IgG subclass isolated from the sera of SLE patients induced IL-6 secretion in proximal renal tubular epithelial cells, which was accompanied by ERK activation [43]. …”

Elevated urinary excretion of immunoglobulins in nonproteinuric patients with type 1 diabetes

“…Moreover, albumin was shown to be nontoxic to proximal tubules (5). Exposure of proximal tubules to IgG (but not to albumin) resulted in the increased inflammatory response in another study (26). In the diabetic kidney, infiltrates of IgGϩ B cells and IgG deposition (colocalizing with C3 staining, macrophage accumulation, and chemokine expression) were demonstrated in diabetic nonobese and db/db mice, contrary to the control mice (6,35).…”