Exosomal CCL2 from Tubular Epithelial Cells Is Critical for Albumin-Induced Tubulointerstitial Inflammation

Abstract

Albuminuria is a key instigator of tubulointerstitial inflammation associated with CKD, but the mechanism through which filtered albumin propagates renal injury remains unclear. In this study, we explored the role in this process of exosome mRNA released from tubular epithelial cells (TECs). Compared with control mice, acute and chronic kidney injury models had more exosomes containing inflammatory cytokine mRNA, particularly the chemokine CCL2, in kidneys and urine. stimulation of TECs with BSA recapitulated this finding. Notably, the internalization of purified TEC exosomes by cultured macrophages increased if TECs were exposed to BSA. Macrophage internalization of exosomes from BSA-treated TECs led to an enhanced inflammatory response and macrophage migration, but CCL2 silencing in TECs prevented these effects. Using a GFP-CCL2 fusion mRNA construct, we observed direct transfer of CCL2 mRNA from TEC exosomes to macrophages. Mice subjected to tail vein injection of purified BSA-treated TEC exosomes developed tubular injury with renal inflammatory cell infiltration. However, injection of exosomes from BSA-treated CCL2-deficient TECs induced less severe kidney inflammation. Finally, in patients with IgA nephropathy, the increase of proteinuria correlated with augmented urinary excretion of exosomes with exaggerated expression of CCL2 mRNA. Moreover, the level of CCL2 mRNA in urinary exosomes correlated closely with levels of renal interstitial macrophage infiltration in these patients. Our studies demonstrate that the increasing release of exosomes that transfer CCL2 mRNA from TECs to macrophages constitutes a critical mechanism of albumin-induced tubulointerstitial inflammation.

hsa‐miR‐500a‐3P alleviates kidney injury by targeting MLKL‐mediated necroptosis in renal epithelial cells

“…The release and uptake of extracellular vesicles play significant roles in disease progression in the kidney (30). A recent study showed that isolated exosomes from bovine serum albumin-treated tubular epithelial cells enhanced the inflammatory response and macrophage migration by transferring CCL2 mRNA, which enhanced albuminuria-induced renal injury (31). In the present study, we isolated circulating exosomes from human subjects and found exosomes from patients with AKIinduced cell damage and inflammation.…”

New insight into the role of extracellular vesicles in kidney disease

“…Intravenous administration of exosomes from normal human kidney tubular cells prevented damage after hypoxic AKI . In contrary to the protective effect, other study found that exosomes from injured TECs accelerated kidney injury through activating macrophage infiltration and activation in tubulointerstitium . Similarly, scratch wounding in TECs induced a significant increase of exosome production, and the secreted exosomes could inhibit wound healing …”

“…Transwell system showed that the exosomes released by glomerular mesangial cells under high glucose condition were involved in podocyte injury. High glucose promoted TGFβ1 loading into exosomes in glomerular mesangial cells, while berberine can reduce the level of TGFβ1 in exosomes and can protect damage of podocytes by reducing apoptosis and increasing adhesion …”

“…Upon exposure to proteinuria, TECs produced increasing exosomes loading with CCL2 mRNA which could be transferred to macrophages and promoted macrophage activation. It may constitute a critical mechanism of albumin‐induced tubulointerstitial inflammation . Interestingly, in tumour microenvironment, exosome‐mimetic nanovesicles derived from M1 macrophages could induce polarization of M2 macrophages to M1 macrophages in vitro and in vivo.…”

“…56,57 In contrary to the protective effect, other study found that exosomes from injured TECs accelerated kidney injury through activating macrophage infiltration and activation in tubulointerstitium. 50 Similarly, scratch wounding in TECs induced a significant increase of exosome production, and the secreted exosomes could inhibit wound healing. 58 Thus, diverse biological effects of exosomes from TECs have been described in different models which might depend on the conditions and functional state of the parent cells.…”