Exploring macrophage cell therapy on Diabetic Kidney Disease

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.

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

“…Similar to this study, it has been found that NGAL KO mice had worse renal damage after IR-induced AKI [86]. Furthermore, NGAL therapy is effective in DN [87]. In this study, macrophage NGAL cell therapy increased the anti-inflammatory molecule IL-10 and decreased the proinflammatory molecule TNF-α, indicating that NGAL overexpressing macrophage therapy could reduce inflammation in DN.…”

Clusterin regulates macrophage expansion, polarization and phagocytic activity in response to inflammation in the kidneys

“…Previous studies also have confirmed that the phagocytic activity of M2 Mφ is more efficient than that of M1 cells. 52,53 They attributed this to the higher activity of M2 Mφ in scavenging debris and tissue remodeling. 54,55 Furthermore, following hypoxia incubation of RAW264.7 cells for 24 h, CLU expression was enhanced (Figure 3), but those of the M1 marker CD80 and the M2 marker CD206 decreased, while the phagocytosis was also increased (data not shown).…”

The influenza virus NS1A binding protein gene modulates macrophages response to cytokines and phagocytic potential in inflammation

“…We already demonstrated that cell therapy with modified macrophages ameliorate kidney damage in different experimental renal pathologies by decreasing the inflammatory scenario 5 – 7 . Given the properties of Ivns1abp-macrophages in actin cytoskeleton stability and the resistance against inflammatory insults, we therefore investigated whether cell therapy with these modified macrophages preserve kidney function and epithelial integrity against the inflammatory damage associated with I/R injury.…”

“…Lastly, given the properties of macrophages overexpressing Ivns1abp in actin cytoskeleton stability and resistance to inflammation and following our previous experience in cellular therapy with macrophages in renal pathology 5 – 7 , we hypothesized that these macrophages could be used as a treatment for damage associated with I/R injury. The experiments revealed that BMDMs that overexpress Ivns1abp were highly protective of renal function as well as the epithelial structure of renal tubules preventing mismatches of actin cytoskeleton loss.…”

“…Latter investigations suggest that targeting macrophage activation and phenotype can lead to new therapies in the treatment of acute and chronic diseases such as obesity, insulin resistance or asthma 3 , 4 . Along the same lines, our group has demonstrated the therapeutic effect of macrophage-cell therapy in different chronic and acute kidney diseases 5 – 7 .…”