CXCR4 Promotes Renal Tubular Cell Survival in Male Diabetic Rats: Implications for Ligand Inactivation in the Human Kidney

Abstract

Binding of the receptor CXCR4 to its ligand stromal cell-derived factor 1 (SDF-1) promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase 9 (MMP-9). In light of the pivotal role that the SDF-1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death. In cultured cells, CXCR4 blockade promoted tubular cell apoptosis, up-regulated Bcl-2-associated death promoter, and prevented high glucose/SDF-1-augmented phosphorylation of the pro-survival kinase, Akt. Although CXCR4 expression was also increased in biopsy tissue from patients with diabetic nephropathy, serine 339 phosphorylation of the receptor, indicative of ligand engagement, was unaffected. Coincident with these changes in receptor expression but not activity, MMP-9 was also up-regulated in diabetic nephropathy biopsies. Supporting a ligand-inactivating effect of the endopeptidase, exposure of cultured cells to recombinant MMP-9 abrogated SDF-1 induced Akt phosphorylation. These observations demonstrate a potentially reno-protective role for CXCR4 in diabetes that is impeded in its actions in the human kidney by the coincident up-regulation of ligand-inactivating endopeptidases. Therapeutically intervening in this interplay may limit tubulointerstitial injury, the principal determinant of renal decline in diabetes.

Contrast Media-Induced Renal Inflammation Is Mediated Through HMGB1 and Its Receptors in Human Tubular Cells

“…A study in the kidney after ischemic acute renal injury showed the expression of CXCR4 in tubular cells (Togel et al, 2005). Siddiqi et al (2015) also confirmed that CXCR4 mRNA and protein increased approximately two to three-folds in the kidneys of diabetic rats compared with control. In addition, the expression of CXCR4 in NRK-52E cells was confirmed by immunoblotting.…”

“…High glucose increased the expression of TLR2/4 in HK-2 cells and played an important role in diabetic nephropathy (Mudaliar et al, 2013). CXCR4 is receptor of Stromal cell-derived factor-1 (SDF-1), which contributes to chemotaxis, activation, and homeostasis of many cells (Siddiqi et al, 2015). HMGB1 promoted recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling through CXCR4 (Schiraldi et al, 2012).…”

“…HMGB1 promoted recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling through CXCR4 (Schiraldi et al, 2012). The expression of CXCR4 was found in NRK-52E cells (Siddiqi et al, 2015). To sum up, inflammatory receptor TLRs and CXCR4 expressed in renal tubular epithelial cells and HMGB1 activates NF-kB leading to the synthesis of proinflammatory cytokines (Klune et al, 2008).…”

Endogenous factors and mechanisms of renoprotection and renal repair

“…35 CXCL12 is in addition elevated after ischaemic reperfusion injury protecting tubular epithelial cells as shown by Stokman et al 36 in animal models using antisense oligonucleotides against CXCL12. 35 CXCL12 is in addition elevated after ischaemic reperfusion injury protecting tubular epithelial cells as shown by Stokman et al 36 in animal models using antisense oligonucleotides against CXCL12.…”

“…Binding of CXCL12, also known as stromal cell-derived factor 1 (SDF-1), to the chemokine receptor 4 (CXCR4) represents another mechanism counteracting apoptosis of renal cells. 35 CXCL12 is in addition elevated after ischaemic reperfusion injury protecting tubular epithelial cells as shown by Stokman et al 36 in animal models using antisense oligonucleotides against CXCL12. CCR7 is linked to CXCR4 and CXCL12 in the protein-protein interaction network and also reported to be involved in antiapoptotic processes in mesangial cells.…”