Semaphorins and Plexins in Kidney Disease

Xia, Jingjing; Worzfeld, Thomas

doi:10.1159/000443645

Cited by 14 publications

(12 citation statements)

References 25 publications

(68 reference statements)

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“…b Each module contained transcripts with similar expression patterns across pre-ischemia, ischemia, and reperfusion conditions. The total number of transcripts in each module is shown response in AKI [34,35]. Integrin and actin signaling pathways linked to Rho signaling related to cytoskeletal remodeling process during cell growth and wound healing were enriched in the reperfusion effect clusters.…”

Section: Som Clustering Analysismentioning

confidence: 99%

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney

Park

Kwon

et al. 2020

BMC Nephrol

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Background Acute kidney injury (AKI) is defined as a sudden event of kidney failure or kidney damage within a short period. Ischemia-reperfusion injury (IRI) is a critical factor associated with severe AKI and end-stage kidney disease (ESKD). However, the biological mechanisms underlying ischemia and reperfusion are incompletely understood, owing to the complexity of these pathophysiological processes. We aimed to investigate the key biological pathways individually affected by ischemia and reperfusion at the transcriptome level. Results We analyzed the steady-state gene expression pattern of human kidney tissues from normal (pre-ischemia), ischemia, and reperfusion conditions using RNA-sequencing. Conventional differential expression and self-organizing map (SOM) clustering analyses followed by pathway analysis were performed. Differential expression analysis revealed the metabolic pathways dysregulated in ischemia. Cellular assembly, development and migration, and immune response-related pathways were dysregulated in reperfusion. SOM clustering analysis highlighted the ischemia-mediated significant dysregulation in metabolism, apoptosis, and fibrosis-related pathways, while cell growth, migration, and immune response-related pathways were highly dysregulated by reperfusion after ischemia. The expression of pro-apoptotic genes and death receptors was downregulated during ischemia, indicating the existence of a protective mechanism against ischemic injury. Reperfusion induced alterations in the expression of the genes associated with immune response such as inflammasome and antigen representing genes. Further, the genes related to cell growth and migration, such as AKT, KRAS, and those related to Rho signaling, were downregulated, suggestive of injury responses during reperfusion. Semaphorin 4D and plexin B1 levels were also downregulated. Conclusions We show that specific biological pathways were distinctively involved in ischemia and reperfusion during IRI, indicating that condition-specific therapeutic strategies may be imperative to prevent severe kidney damage after IRI in the clinical setting.

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Section: Som Clustering Analysismentioning

confidence: 99%

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney

Park

Kwon

et al. 2020

BMC Nephrol

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“…SEMA3A has been reported to play important roles in multiple aspects of renal diseases [7]. For example, urinary SEMA3A has been shown to be an early, predictive biomarker of acute kidney injury (AKI) as well as later-onset AKI and progression of AKI [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Since excess SEMA3A has been reported to be associated with various glomerular diseases [7], we applied the Dox-induced podocytopathy mouse model and examined the change of SEMA3A expression. SEMA3A expression in podocytes was dramatically increased in the Dox group compared to the control group ( Figure 1A).…”

Section: Podocyte Sema3a Expression Is Increased In a Dox-induced Moumentioning

confidence: 99%

“…Class 3 semaphorins are secreted proteins while the others are transmembrane (class 4, 5 and 6) or glycosylphosphatidylinositol-linked proteins (class 7) [6]. Semaphorins were recognized as key regulators of various cellular functions in many tissues, including kidney, heart, bone, and neuron [7,8]. Class 3 semaphorins comprise 7 proteins, which are semaphorin 3A-3G (SEMA3A-3G).…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence has indicated the role of SEMA3A in renal diseases. For example, SEMA3A expression is increased in various glomerular diseases [7]. It has also been suggested that excess SEMA3A binds to NRP1, leading to activation of plexinA, inducing foot process effacement, endothelial injury, and GBM lamination [8,11].…”

Section: Introductionmentioning

confidence: 99%

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Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury

Sang

Tsuji

Inoue-Torii

et al. 2020

IJMS

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Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.

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Plexins

Worzfeld¹

2020

Encyclopedia of Molecular Pharmacology

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Plexins comprise an evolutionary conserved and widely expressed family of transmembrane proteins that serve as receptors for semaphorins. They regulate key cellular functions such as morphology, proliferation, differentiation, and migration and play a pivotal role in cell-cell communication. On the basis of homology, they are grouped into four subfamilies (A-D). Semaphorins are a large family of secreted and membrane-associated proteins. In the mammalian system, five structurally different classes of semaphorins (3-7) have been found (Fig. 1). While the semaphorin-plexin system was initially discovered as a regulator of axonal guidance in the developing nervous system, it has become clear that its physiological and pathophysiological relevance is much larger including the cardiovascular, immune, renal, and bone system as well as cancer (Worzfeld and Offermanns 2014). Basic Mechanisms Both plexins and semaphorins are structurally characterized by the presence of an extracellular sema domain, which contains a seven-blade bpropeller (Fig. 1) (Worzfeld and Offermanns 2014). The sema domain of semaphorins mediates the formation of semaphorin homodimers (Fig. 2). So far, there is no evidence for semaphorin heterodimers or for functional semaphorin monomers. The extracellular domain of plexins forms an autoinhibited ring-like conformation. In contrast to the sema domain of semaphorins, the sema domain of plexins is monomeric and does not dimerize. The cytoplasmic moieties of plexins (600 amino acids) are highly conserved and do not show homology to any other known protein. The interaction between semaphorins and plexins is mediated by the sema domains (Table 1). The semaphorin-plexin binding interface is relatively large, and the binding specificity critically relies on insertions in the b-propeller of the sema domains. Each subunit of a semaphorin dimer binds a monomeric plexin, thereby inducing the formation of plexin dimers and plexin downstream signaling (Fig. 2). Class-3-semaphorins require neuropilins as co-receptors, which stabilize the binding of a class-3-semaphorin to its plexin receptor. Other functionally relevant coreceptors for plexins of the Band D-subfamily include the receptor tyrosine kinases ErbB-2 and Met. Since semaphorins are found both in a membrane-bound form and in a soluble form, plexins

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Semaphorins and Plexins in Kidney Disease

Cited by 14 publications

References 25 publications

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney

Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury

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