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Sang, Y.; Tsuji, K.; Nakanoh, H.; Fukushima, K.; Kitamura, S.; Wada, J. Semaphorin 3A and Kidney Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/49926 (accessed on 03 August 2024).
Sang Y, Tsuji K, Nakanoh H, Fukushima K, Kitamura S, Wada J. Semaphorin 3A and Kidney Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/49926. Accessed August 03, 2024.
Sang, Yizhen, Kenji Tsuji, Hiroyuki Nakanoh, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada. "Semaphorin 3A and Kidney Diseases" Encyclopedia, https://encyclopedia.pub/entry/49926 (accessed August 03, 2024).
Sang, Y., Tsuji, K., Nakanoh, H., Fukushima, K., Kitamura, S., & Wada, J. (2023, October 08). Semaphorin 3A and Kidney Diseases. In Encyclopedia. https://encyclopedia.pub/entry/49926
Sang, Yizhen, et al. "Semaphorin 3A and Kidney Diseases." Encyclopedia. Web. 08 October, 2023.
Semaphorin 3A and Kidney Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13193038

Kidney diseases are worldwide public health problems affecting millions of people. However, there are still limited therapeutic options against kidney diseases. Semaphorin 3A (SEMA3A) is a secreted and membrane-associated protein, which regulates diverse functions, including immune regulation, cell survival, migration and angiogenesis, thus involving in the several pathogeneses of diseases, including eyes and neurons, as well as kidneys. SEMA3A is expressed in podocytes and tubular cells in the normal adult kidney, and recent evidence has revealed that excess SEMA3A expression and the subsequent signaling pathway aggravate kidney injury in a variety of kidney diseases, including nephrotic syndrome, diabetic nephropathy, acute kidney injury, and chronic kidney disease. 

semaphorin 3A neuropilin-1 podocyte diabetic nephropathy

1. Podocytopathy and Diabetic Nephropathy

Podocytes, which have crucial roles in the kidney filtration barrier, line out of the glomerular basement membrane (GBM), prevent urinary protein loss [1]. Podocyte foot processes are linked by slit diaphragms, which regulate cell shape and work as a filtration barrier [2]. Hence, podocyte injury is associated with proteinuria. As indicated above, recombinant SEMA3A injection into adult mice induced nephrotic-range proteinuria [3]; the increase was within 4 h and was resolved within 24 h. TEM analysis revealed the extensive fusion and effacement of podocyte foot processes in kidneys examined 4 h after SEMA3A injection, which were recovered at 48 h, demonstrating that excess circulating SEMA3A may cause podocyte ultrastructural abnormalities, and the permeability of the glomerular filtration barrier is transient and reversible, providing proof of the principle of excess SEMA3A and glomerular disease. In addition, it has also been reported that the SEMA3A-induced downregulation of podocin in a dose-dependent manner decreases the interactions between nephrin, podocin, and CD2-assocaited protein (CD2AP) in cultured podocytes [4]. SEMA3A induced a 10-fold increase in podocyte apoptosis by decreasing the Akt survival pathway [4]. Excess SEMA3A was shown to induce endothelial cell swelling and thickening, lamination of the GBM, and podocyte-foot-process effacement, all of which were transient and reversible upon withdrawal of transgene induction. SEMA3A disrupted podocyte shape in an autocrine fashion, based on podocyte contraction and F-actin collapse [5]. It has been reported that the mechanism under the GBM phenotype change was through increased matrix metalloproteinase 9 expression or the composition of the collagen and laminin chain [6]. Excess SEMA3A caused reversible nephrin downregulation, while the podocin expression and WT1+ nuclei counts were not altered, suggesting that SEMA3A caused decreased nephrin expression without podocyte loss. In addition, GST-binding assays revealed a direct interaction between plexin A and nephrin [5], indicating that extracellular SEMA3A signaling may be directly linked to the slit-diaphragm signaling complex. Increased SEMA3A mRNA and protein expression were found in experimental models of puromycin (PAN)-induced podocyte injury [7].
Diabetic nephropathy (DN) is one of important complications of DM [8], and is a leading cause of CKD and end-stage renal disease (ESRD) worldwide [9][10]. DN is known to cause podocyte injury and generally starts with microalbuminuria, which progresses to GBM thickness, mesangial expansion, macroalbuminuria, and, finally, a decreasing glomerular filtration rate [11][12]. A multifactorial interaction of factors is involved in DN, such as the formation of advanced glycation end products (AGEs), and the renin–angiotensin system (RAAS), further stimulating protein kinase C, and the generation of reactive oxygen species (ROS) [13][14] and microRNAs. It has been reported that urinary SEMA3A excretion was increased early after the induction of diabetes in diabetic mouse models and in diabetic patients with albuminuria, particularly in those with macroalbuminuria [15]. In diabetic mice, podocyte-specific SEMA3A overexpression (SEMA3A+) caused Kimmelstiel-Wilson-like nodular glomerulosclerosis, massive proteinuria and kidney insufficiency [16]. Increased SEMA3A expression was found in db/db kidneys [7], as well as streptozotocin-induced-diabetes mouse kidneys [17]. The genetic ablation and inhibition of SEMA3A signaling ameliorated diabetes-induced kidney dysfunction [15]. Importantly, a SEMA3A inhibitor, xanthofulvin treatment or the deletion of podocyte plexin A1 abrogated diabetic nodular glomerulosclerosis induced by the SEMA3A+ gain of function [16]. A recent study revealed that microRNAs play important roles in DN pathogenesis. miR-15b-5p restored cell proliferation in high-glucose-induced podocytes by downregulating proapoptotic protein markers, Bax and cleavaged caspase-3, and upregulating the antiapoptotic protein Bcl-2 [18]. miR-15b-5p remarkably decreased the high-glucose-induced inflammatory response via the downregulation of cytokines, IL-1β, TNF-α and IL-6. In addition, it was reported that SEMA3A is a direct target of miR-15b-5p, and the beneficial effects of miR-15b-5p were impeded by excess SEMA3A [18]. SEMA3A is also targeted by miR-23b-3p [19] and miR-16-5p [20]. KCNQ1 opposite-strand/antisense transcript 1(KCNQ1OT1), a long non-coding RNA (lncRNA), was recognized as a miR-23b-3p sponge, and KCNQ1OT1 inhibition ameliorated DN by absorbing miR-23b-3p and regulating SEMA3A [19]. It has also been reported that serum lncRNA T-cell factor7 (TCF7) were elevated in patients with DN and TCF7 silencing ameliorated high-glucose-induced podocyte injury by downregulating SEMA3A via miR-16-5p [20]. Collectively, excess SEMA3A is involved in the progression of DN, and SEMA3A targeting may be a potential therapy against DN.

2. Acute Kidney Injury

AKI is recognized as a major public health problem, affecting millions of patients worldwide and leading to higher mortality [21], CKD progression, and sometimes to the new onset of CKD, called the AKI–CKD transition. Kidney ischemia-reperfusion injury (IRI), nephrotoxic agents such as LPS or cisplatin, infection leading to sepsis, and contrast-related injury are major causes of AKI [22]. Currently, AKI is diagnosed according to serum creatinine levels and urine volume [23]. Early prediction before an increase in serum creatinine levels and early treatment are important for patients at risk of AKI. Urinary SEMA3A has been shown to be increased within 6 h after IRI, whereas serum creatinine is increased at 24 h in animals [24]. Urinary SEMA3A was also shown to increase, and peaked at 2 h, after liver-transplantation-induced AKI [25]. Serum SEMA3A in cisplatin-induced AKI was upregulated at 24 h and 48 h. In pediatric patients, AKI was detected 48 h after a cardiopulmonary bypass (CPB) through serum creatinine levels [24], while urine SEMA3A was elevated 2 h after CPB and peaked at 6 h. Moreover, an early increase in urinary SEMA3A levels were associated with clinical outcomes, such as the severity of AKI and the length of a hospital stay [24]. Urinary SEMA3A was compared with other urinary biomarkers, IL-18 [26], L-type fatty acid-binding protein(L-FABP) [27], gelatinase-associated lipocalin (NGAL) [28] and N-acetyl-β-d-glycosaminidase (NAG), in intensive care unit (ICU) admission. These biomarkers showed similar performance in detecting established AKI, later-onset AKI and AKI progression, while urinary SEMA3A was not increased in non-progressive established AKI. Finally, urinary SEMA3A was not increased in sepsis-induced AKI, while levels of other urinary biomarkers were increased [29][30]. An increase in urinary SEMA3A was also reported in contrast-induced acute kidney injury [31]. Among 168 patients who underwent percutaneous coronary intervention (PCI), 20 patients developed AKI. Both urinary SEMA3A and NGAL levels were significantly elevated at 2 h and 6 h post-PCI procedure, and peaked at 2 h post-PCI in the AKI patients, which was much earlier than the rise in serum creatinine levels at 48–72 h post-PCI. Further receiver operating characteristic (ROC) analyses of SEMA3A at 2 h after PCI showed a better predictive sensitivity and specificity compared to NGAL. These results indicate that urinary SEMA3A may be useful as an early and predictive biomarker for AKI.
In addition to biomarkers, SEMA3A signaling is also expected to be a therapeutic target. SEMA3A expression was increased after LPS-induced AKI in mouse tubular epithelial cells, as well as in an LPS-treated rat-kidney-proximal-tubular-epithelial-cell line in vitro via Rac1/nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) p65 and JNK pathways [32]. In addition, the inhibition of SEMA3A by (-)-epigallocatechin-3-gallate (EGCG) could significantly ameliorate LPS-induced kidney inflammation and apoptosis [32]. It is also reported that genetic silencing and the pharmacological inhibition of SEMA3A ameliorated kidney injury from IRI by inhibiting inflammation and epithelial cell apoptosis [33]. These observations indicate an underling signaling pathway of SEMA3A and the potential utility of a SEMA3A inhibitor as a therapeutic agent for regulating inflammation and apoptosis in AKI. G-protein-coupled receptors (GPCRs) are known to participate in plenty of physiologic functions, and some GPCRs have critical roles in the regulation of kidney function. Among them, Gpr97 is a newly identified adhesion GPCR. Gpr97 was upregulated in IRI-induced AKI mice kidneys [34]. Both in vivo and vitro study have revealed that Gpr97 deficiency attenuated AKI-induced kidney injury by regulating SEMA3A signaling. It was also reported that curcumin, well known for its antioxidant and anti-inflammatory properties, and 12/15 lipoxygenase inhibitor-LOXblock-1 ameliorated IRI-induced AKI by reducing inflammatory processes, oxidative stress and apoptosis, and the effects were through the suppression of the SEMA3A signaling pathway [35]. Another study highlighted the protective effects of human-bone-marrow-derived mesenchymal stem cell exosomes in kidney IRI by delivering miR-199a-3p to kidney cells [36]. The mechanism involved downregulating Sema3A expression and activating Akt and extracellular signal-regulated kinase (ERK) signaling pathways, ultimately leading to reduced apoptosis and improved kidney function. These reports indicate a potential avenue for developing new therapeutic strategies to target SEMA3A signaling for AKI.

3. Chronic Kidney Disease

CKD is characterized by progressive damage and a loss of kidney function, in which parenchymal cell loss, chronic inflammation, fibrosis and the reduced regenerative capacity of the kidney are involved in its progression [37]. It was reported that urinary SEMA3A levels were positively correlated with the urine albumin-to-creatinine ratio and serum creatinine levels in hypertensive patients [38]. In the study, patients with CKD showed higher urinary SEMA3A levels compared to those without CKD. Kidney fibrosis is the common pathological pathway of kidney diseases. Researchers evaluated SEMA3A signaling by usingunilateral ureteral obstruction (UUO) mouse model, a kidney fibrosis model [39]. After UUO surgery, SEMA3A expression in the proximal tubular area and NRP1 expression in the fibroblast and tubular cells were increased. The expression of a myofibroblast marker, tenascin-C, and kidney fibrosis were increased in UUO kidneys, all of which were ameliorated by a SEMA3A inhibitor through the regulation of JNK signaling [39]. One of the important mechanisms in kidney tubulointerstitial fibrosis is the kidney tubular epithelial–mesenchymal transition (EMT) process, where kidney tubular epithelial cells lose their cell-to-cell membrane connection and their structural polarity to become a spindle-shaped mesenchymal-like phenotype [40].

4. Systemic Lupus Erythematosus

SEMA3A also regulates immune systems, especially enhancing T-cell and B-cell regulatory properties [41]. Hence, it was reported that SEMA3A is involved in the pathogenesis of autoimmune diseases, including SLE [42], rheumatoid arthritis [43] and Sjogren’s syndrome [44]. SLE is a multi-system autoimmune disease characterized by the aberrant activity of the immune system, and presents with a wide range of clinical manifestations including skin, synovia, brain and kidney [45]. Of note, an analysis of SEMA3A immunostaining in kidneys from patients with lupus nephritis (LN) revealed an increase in SEMA3A expression in patients with LN, while SEMA3A expression was negatively associated with clinical–pathological parameters, including proteinuria and kidney function [46]. In contrast, another study indicated that serum SEMA3A levels in SLE patients were lower than in normal individuals [42]. Aiming to establish a regulatory/protective role for SEMA3A in SLE, serum SEMA3A was assessed in patients with SLE, and this level was compared with SLE disease activity [42], where serum SEMA3A levels were lower in SLE patients compared to those in normal controls. In addition, altered serum SEMA3A levels were found to be inversely correlated with SLE disease activity, mainly with kidney damage and the presence of anti-cardiolipin antibodies. These findings suggest an important role of SEMA3A in SLE.
It was reported that SEMA3A downregulated autoimmune responses by suppressing the over-activity of both B and T cells [47][48]. SEMA3A levels in the B-regulatory cells of patients with SLE were smaller compared to those of normal individuals. Toll-like receptor (TLR)-9 expression could possibly be modulated in the memory B cells of SLE patients, which is associated with the production of inflammatory cytokines such as IL-6 and anti-dsDNA [49][50]. SEMA3A co-cultured with purified B cells from SLE patients significantly reduced TLR-9 expression, supporting the idea that SEMA3A may regulate B-cell autoimmunity in SLE [42]. Serum SEMA3A levels were decreased in SLE while increased in rheumatoid arthritis and Sjogren’s syndrome, compared to healthy controls. How about urinary SEMA3A levels? A study analyzed urinary SEMA3A levels in 38 patients with SLE [51]. Among them, 13 patients had kidney involvement. Urinary SEMA3A levels were lower in SLE patients compared to healthy volunteers, and especially lower in SLE patients with LN than in patients without nephritis, indicating that urinary SEMA3A is inversely correlated with proteinuria and SLE disease activity. The aberrant expression of SEMA3A urine and serum levels in SLE may suggest important roles of SEMA3A in SLE disease activity. Indeed, it was reported that SEMA3A injections in a New Zealand black (NZB)/W mice model of LN delayed the appearance of proteinuria and reduced kidney damage, as well as causing a decrease in immune complex deposition in the glomeruli, indicating the protective effect of SEMA3A in LN [52].

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Subjects: Urology & Nephrology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Yizhen Sang
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Kenji Tsuji
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Hiroyuki Nakanoh
,
Kazuhiko Fukushima
,
Shinji Kitamura
,
Jun Wada
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Update Date: 09 Oct 2023
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