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Signal regulatory protein ? protects podocytes through promoting autophagic activity.

ABSTRACT: High autophagic activity in podocytes, terminally differentiated cells which 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 ? (SIRP?) plays a key role in promoting podocyte autophagy. Unlike other glomerular cells, podocytes strongly express SIRP?, which is, however, downregulated in patients with focal segmental glomerulosclerosis and mice with experimental nephropathy. Podocyte SIRP? levels are inversely correlated with the severity of podocyte injury and proteinuria but positively with autophagy. Compared to wild-type littermates, Sirpa-deficient mice display greater age-related podocyte injury and proteinuria and develop more rapid and severe renal injury in various models of experimental nephropathy. Mechanistically, podocyte SIRP? strongly reduces Akt/GSK-3?/?-catenin signaling, leading to an increase in autophagic activity. Our findings thus demonstrate a critical protective role of SIRP? in podocyte survival via maintaining autophagic activity.

SUBMITTER: Li L

PROVIDER: S-EPMC6538339 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Signal regulatory protein α protects podocytes through promoting autophagic activity.

Li Limin L Liu Ying Y Li Shan S Yang Rong R Zeng Caihong C Rong Weiwei W Liang Hongwei H Zhang Mingchao M Zhu Xiaodong X Kidder Koby K Liu Yuan Y Liu Zhihong Z Zen Ke K

JCI insight 20190319

High autophagic activity in podocytes, terminally differentiated cells which 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 express SIRPα, which is, however, downregulated in patients with f ...[more]

PMID: 30888336

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Project description:BackgroundMuscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD.MethodsWe assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle-specific or adipose tissue-specific KO of SIRPα. Metabolic responses were confirmed in primary cultures of adipose cells.ResultsIn mice with CKD, SIRPα expression was increased in WAT (three-fold, P < 0.05), and this was associated with precursors of cachexia: 'pathologic browning', thermogenesis, and a two-fold activation of protein kinase A (P < 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRPα global KO and CKD or acute diabetes experienced improved insulin signalling and activation of pAkt plus 'physiologic browning' of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (P < 0.05) than did wild-type mice with CKD. In muscle-specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (P < 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose-specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over two-fold (P < 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRPα signalling are suggested by our findings that include increased SIRPα expression in muscle and adipose tissues (P < 0.05 vs. healthy controls) plus higher SIRPα levels in the serum of patients with CKD (2.4-fold, P=0.000017 vs. healthy controls).ConclusionsOur results show that SIRPα plays an important role as an anti-insulin mediator regulating pathways to cachexia. In muscle-specific SIRPα KO, changes in SIRPα serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRPα may prevent cachexia in patients with CKD or acute diabetes.

Project description:Glioblastoma (GBM) is the most common malignant primary brain tumor. Glioblastomas contain a large non-cancerous stromal compartment including various populations of tumor-associated macrophages and other myeloid cells, of which the presence was documented to correlate with malignancy and reduced survival. Via single-cell RNA sequencing of human GBM samples, only very low expression of PD-1, PD-L1 or PD-L2 could be detected, whereas the tumor micro-environment featured a marked expression of signal regulatory protein alpha (SIRPα), an inhibitory receptor present on myeloid cells, as well as its widely distributed counter-receptor CD47. CITE-Seq revealed that both SIRPα RNA and protein are prominently expressed on various populations of myeloid cells in GBM tumors, including both microglia- and monocyte-derived tumor-associated macrophages (TAMs). Similar findings were obtained in the mouse orthotopic GL261 GBM model, indicating that SIRPα is a potential target on GBM TAMs in mouse and human. A set of nanobodies, single-domain antibody fragments derived from camelid heavy chain-only antibodies, was generated against recombinant SIRPα and characterized in terms of affinity for the recombinant antigen and binding specificity on cells. Three selected nanobodies binding to mouse SIRPα were radiolabeled with 99mTc, injected in GL261 tumor-bearing mice and their biodistribution was evaluated using SPECT/CT imaging and radioactivity detection in dissected organs. Among these, Nb15 showed clear accumulation in peripheral organs such as spleen and liver, as well as a clear tumor uptake in comparison to a control non-targeting nanobody. A bivalent construct of Nb15 exhibited an increased accumulation in highly vascularized organs that express the target, such as spleen and liver, as compared to the monovalent format. However, penetration into the GL261 brain tumor fell back to levels detected with a non-targeting control nanobody. These results highlight the tumor penetration advantages of the small monovalent nanobody format and provide a qualitative proof-of-concept for using SIRPα-targeting nanobodies to noninvasively image myeloid cells in intracranial GBM tumors with high signal-to-noise ratios, even without blood-brain barrier permeabilization.

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Signal regulatory protein ? protects podocytes through promoting autophagic activity.

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Signal regulatory protein α protects podocytes through promoting autophagic activity.

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