Abstract
Alternatively activated macrophages (M2) have regenerative properties and shown promise as cell therapy in chronic kidney disease. However, M2 plasticity is one of the major hurdles to overcome. Our previous studies showed that genetically modified macrophages stabilized by neutrophil gelatinase‐associated lipocalin (NGAL) were able to preserve their M2 phenotype. Nowadays, little is known about M2 macrophage effects in diabetic kidney disease (DKD). The aim of the study was to investigate the therapeutic effect of both bone marrow‐derived M2 (BM‐фM2) and ф‐NGAL macrophages in the db/db mice. Seventeen‐week‐old mice with established DKD were divided into five treatment groups with their controls: D+BM‐фM2; D+ф‐BM; D+ф‐NGAL; D+ф‐RAW; D+SHAM and non‐diabetic (ND) (db/‐ and C57bl/6J) animals. We infused 1 × 106 macrophages twice, at baseline and 2 weeks thereafter. BM‐фM2 did not show any therapeutic effect whereas ф‐NGAL significantly reduced albuminuria and renal fibrosis. The ф‐NGAL therapy increased the anti‐inflammatory IL‐10 and reduced some pro‐inflammatory cytokines, reduced the proportion of M1 glomerular macrophages and podocyte loss and was associated with a significant decrease of renal TGF‐β1. Overall, our study provides evidence that ф‐NGAL macrophage cell therapy has a therapeutic effect on DKD probably by modulation of the renal inflammatory response caused by the diabetic milieu.
Highlights
Chronic kidney disease (CKD) has been recognized as a major health problem worldwide[1] and there is still a global rising incidence and prevalence.[2]
Our study provides evidence that ф‐neutrophil gelatinase‐associated lipocalin (NGAL) macrophage cell therapy has a therapeutic effect on Diabetic kidney disease (DKD) probably by modulation of the renal inflammatory response caused by the diabetic milieu
We have previously demonstrated that anti‐inflammatory effects induced by hepatocyte growth factor (HGF) gene therapy enhanced the presence of bone marrow‐derived M2 (BM‐ΦM2) macrophages in the glomeruli of diabetic mice and halted DKD progression
Summary
Chronic kidney disease (CKD) has been recognized as a major health problem worldwide[1] and there is still a global rising incidence and prevalence.[2]. The advanced form of DKD displays prominent transforming growth factor (TGF‐β) up‐regulation, mesangial expansion and glomerulosclerosis.[5] TGF‐β1 increases extracellular matrix accumulation through the stimulation of collagen IV and fibronectin production,[6] resulting in interstitial fibrosis and glomerular sclerosis. We investigate an alternative macrophage therapy transduced with Neutrophil gelatinase‐associated lipocalin (NGAL), which is a M2 phenotypically stabilized cell line overexpressing the anti‐inflammatory cytokine IL‐10 and showing low TGF‐β secretion.[23]
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