Expression of Functional CCR and CXCR Chemokine Receptors in Podocytes

Abstract

Chemokines and their receptors play an important role in the pathogenesis of acute and chronic glomerular inflammation. However, their expression pattern and function in glomerular podocytes, the primary target cells in a variety of glomerulopathies, have not been investigated as of yet. Using RT-PCR, we now demonstrate the expression of CCR4, CCR8, CCR9, CCR10, CXCR1, CXCR3, CXCR4, and CXCR5 in cultured human podocytes. Stimulation of these receptors induced a concentration-dependent biphasic increase of the free cytosolic calcium concentration in podocytes in culture. In addition, we demonstrate that podocytes release IL-8 in the presence of FCS and that IL-8 down-regulates cell surface CXCR1. Chemokine stimulation of the detected CCRs and CXCRs increased activity of NADPH-oxidase, the primary source of superoxide anions in podocytes. Immunohistochemistry studies revealed only diffuse and weak CXCR expression in healthy human glomerula. In contrast, in membranous nephropathy, a characteristic podocyte disorder, the expression of CXCR1, CXCR3, and CXCR5 is up-regulated in podocytes. In conclusion, podocytes in culture and podocytes in human kidney sections express a set of chemokine receptors. The release of oxygen radicals that accompanies the activation of CCRs and CXCRs may contribute to podocyte injury and the development of proteinuria during membranous nephropathy.

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

“…Because nuclear HIF1␣ was associated with CXCR4 expression in podocytes of NSC biopsy specimens, we went on to study CXCR4 expression in podocytes in vitro. In cultured human and murine podocytes, we found a low but constitutive expression of CXCR4/Cxcr4, as was also reported by Huber et al 51 Hypoxia in vitro stabilized HIF1␣ and HIF2␣ protein and induced CXCR4/Cxcr4 mRNA expression in podocytes. In our experiments we used HIF1␣ as a global biological marker of hypoxia.…”

“…For IgAN and membranous nephropathy, the absence of prominent CXCR4 expression in glomeruli had been reported previously. 8,51 Although FSGS is characterized by glomerular sclerosis similar to NSC, CXCR4 mRNA was not consistently induced in glomeruli from biopsy specimens of patients with primary FSGS. Although immunohistological analysis also revealed CXCR4 positivity of podocytes in FSGS biopsy specimens, the nuclear HIF1␣ staining in these biopsy specimens seemed restrained and heterogeneous.…”

Mononuclear Cell-Infiltrate Inhibition by Blocking Macrophage-Derived Chemokine Results in Attenuation of Developing Crescentic Glomerulonephritis

“…28 The expression of chemokine receptors such as CXCR1, CXCR3, and CXCR5 is up-regulated in podocytes in patients with membranous nephropathy. 29 Macrophage-derived chemokine (MDC)/stimulated Tcell chemotactic protein (STPC-1, CCL22) is a newly identified CC chemokine expressed by dendritic cells, B and T cells, and M . MDC shares less than 35% identity with any of the known chemokines, and has a tissue expression distribution nearly identical to that of thymusand activation-regulated chemokine (TARC); like TARC, it has been shown to bind to CC receptor 4 (CCR4).…”

Role of the CXCR4/CXCL12 Axis in Lymphangioleiomyomatosis and Angiomyolipoma

“…Primers were designed to target all known chemokine receptors (Table I) (25)(26)(27)(28)(29). RT-PCR was performed in three primary AML-derived cell lines from two separate donors and the immortalized AML-derived line SV7 tert AML.…”