Autophagy activity and expression pattern of autophagy-related markers in the podocytes of patients with lupus nephritis: association with pathological classification

Abstract

Objective: To identify the significance of autophagy in lupus nephritis (LN). Methods: The number of autophagosomes in podocytes was counted and the expression of multiple molecular markers associated with autophagy was evaluated in LN specimens: in renal biopsy specimens from 90 patients with LN and 15 healthy controls, autophagosomes in podocytes were counted using transmission electron microscopy and the expression levels of four autophage related proteins including Beclin-1, microtubule-associated protein light chain 3 (LC3), autophagy-related gene 7 (Atg7), and UNC-51-like kinase 1 (ULK1) were measured using immunohistochemistry. Results: The number of autophagosomes in patients with LN types III, IV, and combined V–IV type were significantly higher than in controls ( p < 0.0001; p < 0.0001; p = 0.009, respectively). However, the autophagosomes numbers in patients with II and V types LN were significantly lower than controls (both p < 0.0001). Various levels of marker expression were identified, and they correlated significantly with LN pathology classifications. Moreover, the percentage of marker expression in LN types III, IV and V-IV were significantly higher than controls ( p < 0.05), while that in types II and V were lower than controls, although the difference for LC3 and ULK1 was not statistically significant. Conclusions: Autophagy activity and expression pattern of autophagy-related markers in podocytes were significantly positively correlated with LN of types III, IV, and V–IV, but negatively correlated with II and V types. Therefore autophagy could be a useful predictor of LN pathology type, and be informative and helpful in the development of treatment strategies in clinical settings.

Catalpol Ameliorates Podocyte Injury by Stabilizing Cytoskeleton and Enhancing Autophagy in Diabetic Nephropathy

“…Autophagy is a highly conserved intracellular catabolic process for degradation of proteins and organelles via the lysosomal pathway (Mizushima and Komatsu, 2011;Mizushima et al, 2008). As terminally differentiated cells, podocytes exhibit a high level of basal autophagy, which play a pivotal role for maintaining podocyte's homeostasis (Hartleben et al, 2010;Yasuda-Yamahara et al, 2015;Jin et al, 2019). Previous studies have shown that podocyte autophagy insufficiency is found in diabetic patients accompanied by massive proteinuria, and impaired podocyte autophagy exacerbated proteinuria in DN, these studies indicate the importance of podocyte autophagy in the pathogenesis of DN (Kume and Koya, 2015;Lenoir et al, 2015;Tagawa et al, 2016).…”

An artificial neural network model based on autophagy-related genes in childhood systemic lupus erythematosus

“…HSP8A is one of the participants in the chaperonemediated autophagy (CAM) process, and studies have shown that CAM is involved in SLE and that adjustment of over-activated CAM is beneficial for SLE [26]. ULK1 was significantly higher in patients with lupus nephritis type IV and V-IV than in normal controls (p < 0.05), and its involvement in autophagy-related pathways influences the pathological process of lupus nephritis [27]. whereas the relationship between the other 5 autophagyrelated genes and SLE has not been elucidated.…”

miR-20a Overexpression in Adipose-Derived Mesenchymal Stem Cells Promotes Therapeutic Efficacy in Murine Lupus Nephritis by Regulating Autophagy

“…mTOR is a transcriptional regulator of autophagy, and inactive mTOR is a key signal for autophagosome biogenesis by activating the ULK kinase complex that occurs in conjunction with the PIK3C3-BECN1-ATG14 complex [ 17 ]. Autophagy is the lysosome-dependent pathway for protein degradation and is impaired in response to metabolic stresses such as autoimmune disease, certain kidney diseases, cancer, and neurodegeneration [ 30 ]. A recent study showed that Treg cells in SLE patients exhibited increased mTOR pathway activities, whereas autophagy and the suppressor function of Treg cells were diminished [ 31 ].…”

“…Liang et al showed deficient autophagy, which was evident by LC3-II and p62 expression and the number of autophagosomes in the MPC5 cells cultured with the IgAN supernatant, along with the upregulated expression of cleaved caspase-3 and a higher apoptosis rate [ 34 ]. However, Jin et al reported that the autophagy activity and expression pattern of autophagy-related markers in podocytes are significantly positively correlated with patients with LN types III, IV, and V–IV but negatively correlated with types II and V [ 30 ]. In the current study, there was a relatively high level of C3/IgG deposits in the glomeruli, and further research showed that podocyte injury occurs in the lupus group, and ADSC/miR-20a-ADSC treatment prevents podocyte damage.…”