Sphingosine-1-phosphate pathway in renal fibrosis

Zhang, Xiwen; Ritter, Joseph K.; Li, Ningjun

doi:10.1152/ajprenal.00596.2017

Cited by 33 publications

(24 citation statements)

References 55 publications

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“…Recent studies support an important role for S1P in renal diseases, including renal fibrosis (reviewed in Ref. [ 54 ]), nephrotic syndrome [ 8 , 9 ] and other glomerular diseases such as IgA nephropathy and lupus nephritis [ 55 , 56 ]. Early studies of streptozotocin (STZ)-treated rats revealed increased levels of S1P in isolated glomeruli during initial stages of DKD [ 57 ].…”

Section: Sphingolipid Signaling In Glomerular Diseasementioning

confidence: 99%

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Mitrofanova

Drexler

Merscher

et al. 2020

Journal of Cellular Signaling

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Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.

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Section: Sphingolipid Signaling In Glomerular Diseasementioning

confidence: 99%

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Mitrofanova

Drexler

Merscher

et al. 2020

Journal of Cellular Signaling

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“…The explanation for this discrepancy could be the different selectivity in S1P receptors between S1P and the agonist FTY720 used in the above study. The FTY720 does not act on S1PR2 [47], whereas the S1PR2-mediated signaling has been shown to play a very important role in the kidney damage [15,48]. The renal protection by SphK1 KO in the present study is probably through the inhibition of S1PR2-mediated signaling when S1P level is reduced.…”

Section: Discussionmentioning

confidence: 47%

“…One of the significant effects by S1P is its role in fibrosis as evidence shows interaction between S1P signaling and TGF-β1 signaling to form a vicious cycle in fibrosis [15]. Fibrotic genesis is the crucial pathological process in chronic kidney diseases.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, SphK1 level can be increased by TGF-β1 activation of Smad complex to increase S1P production. The increased S1P production may amplify fibrogenetic effects [1,15,16]. Although S1P signaling has been shown to participate in the pathogenesis of various kidney diseases, there is lack of evidence demonstrating the role of endogenous SphK1 in kidney damage in a hypertensive model in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Detrimental role of sphingosine kinase 1 in kidney damage in DOCA-salt hypertensive model: evidence from knockout mice

Lyu

Wang

et al. 2020

BMC Nephrol

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Background: Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingolipids and produced by sphingosine kinases (SphK1 and SphK2). SphK1/S1P pathway is implicated in the progression of chronic kidney disease. However, the role of SphK1/S1P pathway in renal injury in hypertension has not been reported. This study tested the hypothesis that SphK1/S1P pathway mediates the kidney damage in DOCA-salt hypertensive mice. Methods: Male wild type (WT) C57BL6 and SphK1 knockout (KO) mice were subjected to unilateral nephrectomy, subcutaneous implant containing 50 mg of deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water for 7 weeks. At the end of experiments, blood pressure data, 24 h urine and kidney samples were collected. Renal mRNA levels of SphK1 were measured by real-time RT-PCR. Markers for fibrogenesis and immune cell infiltration in kidneys were detected using Western blot and immunohistochemistray analysis, respectively. The glomerular morphological changes were examined in kidney tissue slides stained with Periodic-Acid Schiff. Four groups were studied: wild type control (WT-C), WT-DOCA, KO-C and KO-DOCA. Results: The renal SphK1 mRNA expression was significantly upregulated in WT-DOCA mice, whereas this upregulation of renal SphK1 mRNA was blocked in KO-DOCA mice. There was no difference in DOCA-salt-induced hypertension between WT and KO mice. The urinary albumin was increased in both DOCA-salt groups. However, the albuminuria was significantly lower in KO-DOCA than in WT-DOCA group. There were increases in glomerulosclerosis indices in both DOCA-salt groups, whereas the increases were also significantly lower in KO-DOCA than in WT-DOCA mice. Renal protein levels of α-smooth muscle actin were upregulated in both DOCA-salt groups, but the increase was significant lower in KO-DOCA than in WT-DOCA group. The increased staining areas of collagen detected by Sirius Red-staining in kidney tissue sections were also attenuated in KO-DOCA compared with WT-DOCA mice. In contrast, the increased infiltration of CD43+ (a T cell marker) or CD68+ (a macrophage marker) cells in DOCA-salt kidneys showed no significant difference between WT-DOCA and KO-DOCA mice. Conclusions: SphK1/S1P signaling pathway mediates kidney damage in DOCA-salt hypertensive mice independent of blood pressure and immune modulation.

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“…Enrichment analysis showed that the genes in module 1-4 were mainly associated with type I interferon signaling pathway, fibrinolysis, and extracellular matrix organization, specifically inflammatory response and immune response in cluster rank 4 ( Table 1). Previous studies have reported these GO terms to be related to kidney or tubular epithelial cell damage [19,20]. Therefore, genes included in the four clusters were more suspectable to participate in the triggering of injury mechanism of renal tubule-interstitium compared to other DEGs.…”

Section: Integration Of Protein-protein Interaction (Ppi) Network Andmentioning

confidence: 89%

The Key Candidate Genes in Tubulointerstitial Injury of Chronic Kidney Diseases (CKD) Patients as Determined by Bioinformatic Analysis

Wang¹,

Shen

Pan³

et al. 2019

Preprint

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Background: Tubulointerstitial injury (TIL) is common in chronic kidney disease (CKD), which in turn, leads to loss of renal function. The aims of present study were to screen critical genes with tubulointerstitial lesion in CKD by weighted gene correlation network analysis (WGCNA). Methods: GSE104954 gene expression data downloaded from GEO database were used for analysis for differential expression genes(DEGs); Meanwhile, 90 expression data of tubulointerstitial samples in GSE47185 combined with clinic information were applied to WGCNA. According to the enrichment analysis and relationship with estimated glomerular filtration rate (eGFR), the eGFR-associated modules were defined, and the hub gene is selected according to the average intramodular connectivity (Kwithin); Clinical data from Nephroseq were obtained to further validate the relationship between CKD and hub genes. Results: Totally 294 DEGs were screened. Using the WGCNA, we identified 15 co-expressed modules, the blue, brown and yellow modules exhibited strongly association with eGFR, and were significantly enriched in several signaling pathways that have been reported involved in pathogenesis of CKD. Furthermore, it was found that the 4 genes (PLG, ITGB2, CTSS and CCL5) was one of the DEGs which also be identified as hub genes according to Kwithin. Finally, the Nephroseq online tool showed that the tubulointerstitial expression levels of PLG significantly positively correlated with the eGFR, while ITGB2, CTSS and CCL5 connected negatively to the eGFR. Conclusion: WGCNA is an efficient approach to system biology. By this procedure, the present study improved the understanding of the transcriptome status of renal tubulointerstitial injury in CKD.

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Sphingosine-1-phosphate pathway in renal fibrosis

Cited by 33 publications

References 55 publications

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Detrimental role of sphingosine kinase 1 in kidney damage in DOCA-salt hypertensive model: evidence from knockout mice

The Key Candidate Genes in Tubulointerstitial Injury of Chronic Kidney Diseases (CKD) Patients as Determined by Bioinformatic Analysis

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