Signal regulatory protein α protects podocytes through promotion of autophagic activity
Limin Li, Ying Liu, Shan Li, Rong Yang, Caihong Zeng, Weiwei Rong, Hongwei Liang, Mingchao Zhang, Xiaodong Zhu, Koby Kidder, Yuan Liu, Zhihong Liu, Ke Zen
Limin Li, Ying Liu, Shan Li, Rong Yang, Caihong Zeng, Weiwei Rong, Hongwei Liang, Mingchao Zhang, Xiaodong Zhu, Koby Kidder, Yuan Liu, Zhihong Liu, Ke Zen
View: Text | PDF
Research Article Nephrology

Signal regulatory protein α protects podocytes through promotion of autophagic activity

Abstract

High autophagic activity in podocytes, terminally differentiated cells that serve as main components of the kidney filtration barrier, is essential for podocyte survival under various challenges. How podocytes maintain such a high level of autophagy, however, remains unclear. Here we report that signal regulatory protein α (SIRPα) plays a key role in promoting podocyte autophagy. Unlike other glomerular cells, podocytes strongly expressed SIRPα, which was, however, downregulated in patients with focal segmental glomerulosclerosis and mice with experimental nephropathy. Podocyte SIRPα levels were inversely correlated with the severity of podocyte injury and proteinuria but positively with autophagy. Compared with WT littermates, Sirpa-deficient mice displayed greater age-related podocyte injury and proteinuria and developed more rapid and severe renal injury in various models of experimental nephropathy. Mechanistically, podocyte SIRPα strongly reduced Akt/GSK-3β/β-catenin signaling, leading to an increase in autophagic activity. Our findings thus demonstrate a critical protective role of SIRPα in podocyte survival via maintenance of autophagic activity.

Authors

Limin Li, Ying Liu, Shan Li, Rong Yang, Caihong Zeng, Weiwei Rong, Hongwei Liang, Mingchao Zhang, Xiaodong Zhu, Koby Kidder, Yuan Liu, Zhihong Liu, Ke Zen

×

Figure 4

Decrease of SIRPα in podocytes of mice and humans under nephropathy.

Options: View larger image (or click on image) Download as PowerPoint
Decrease of SIRPα in podocytes of mice and humans under nephropathy. (A)...
(A) SIRPα level in glomerulus of mice with PAN, ADR, and STZ treatment over time. Immunoblots are representative of 3 independently performed experiments. Histograms show quantification of SIRPα level. (B) Immunofluorescence staining of SIRPα and nephrin in glomerulus of mice treated with PAN, ADR, and STZ for 2, 4, and 6 weeks (W) respectively. Quantification of SIRPα and nephrin levels in glomerulus was performed by counting approximately 10 glomeruli from 3 independent determinations. Data in A and B represent mean ± SEM from 3 independent experiments, and P value was analyzed by ANOVA with Tukey-Kramer test and 2-tailed Student’s t test, respectively. (C) Colocalization and expression level of SIRPα and nephrin in podocytes of healthy control and FSGS patients. (D) Glomerular immunohistochemistry staining of SIRPα in FSGS patients with low proteinuria (n = 9) and with high proteinuria (n = 8). Histogram represents quantification of glomerular SIRPα staining in the 2 groups of patients. Data represent mean ± SEM, and P value was analyzed by 2-tailed Student’s t test. (E, F, and G) Correlation analysis between SIRPα and albumin level, albumin/creatinine ratio (A/C), and podocyte number; r and P values were analyzed by Pearson’s correlation analysis; red and black plots represent FSGS patients with low and high proteinuria, respectively. In Scale bars in B, C, and D: 25 μm.**P < 0.01.