Loss of sphingosine kinase 2 enhances Wilm's tumor suppressor gene 1 and nephrin expression in podocytes and protects from streptozotocin-induced podocytopathy and albuminuria in mice

Imeri, Faik; Tanturovska, Bisera Stepanovska; Schwalm, Stephanie; Saha, Suparna; Zeng-Brouwers, Jinyang; Pavenstädt, Herrmann; Pfeilschifter, Josef; Schaefer, Liliana; Huwiler, Andrea

doi:10.1016/j.matbio.2021.05.003

Cited by 15 publications

(22 citation statements)

References 70 publications

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“…SphK1 was overexpressed in podocyte from diabetic patients, while SphK1-deficient mice developed a more severe DN [ 206 ], suggesting a protective role of SphK1 for podocytopathy in DN. However, SphK2-knockdown has recently been shown to protect against diabetic podocyte injury and albuminuria [ 207 ]. These data indicate that SphK1 may protect and SphK2 may contribute to the progression of DN.…”

Section: Interaction Between Ros and S1p In Oxidant-induced Kidney In...mentioning

confidence: 99%

“…However, SphK2 deficiency rendered HEK cells resistant to serum deprivation and TNF-α [ 222 ], which produce ROS/ceramide. In addition, depletion of SphK2 prevented diabetic podocyte injury [ 207 ]. Thus, an apoptotic role of SphK2 may depend on types of kidney cells and oxidant stimuli.…”

Section: Roles Of Mitochondria and Cell Signaling Pathways For S1p-in...mentioning

confidence: 99%

“…Targeting enzymes that generate ceramide and S1P to restore a rheostat of ceramide-S1P have been considered as a therapeutic strategy in various diseases (reviewed in [ 283 , 284 ]). In the same line, the application of compounds that can reduce the ratio of ceramide/S1P by targeting the enzymes involved in ceramide production and SphKs would be beneficial to prevent oxidant-induced kidney injury ( Table 4 ) [ 27 , 43 , 62 , 66 , 71 , 74 , 75 , 76 , 78 , 85 , 94 , 198 , 200 , 207 , 219 , 226 , 260 , 264 , 281 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 ]. Among these compounds, fumonisin B1, for the treatment of acute rejection, where ROS are involved, and fingolimod (FTY720) have only been used in kidney transplant recipients [ 294 , 295 ].…”

Section: A Rheostat Of Ceramide-s1p In the Regulation Of Oxidative St...mentioning

confidence: 99%

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A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Ueda

2022

IJMS

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Reactive oxygen species (ROS) modulate sphingolipid metabolism, including enzymes that generate ceramide and sphingosine-1-phosphate (S1P), and a ROS-antioxidant rheostat determines the metabolism of ceramide-S1P. ROS induce ceramide production by activating ceramide-producing enzymes, leading to apoptosis, while they inhibit S1P production, which promotes survival by suppressing sphingosine kinases (SphKs). A ceramide-S1P rheostat regulates ROS-induced mitochondrial dysfunction, apoptotic/anti-apoptotic Bcl-2 family proteins and signaling pathways, leading to apoptosis, survival, cell proliferation, inflammation and fibrosis in the kidney. Ceramide inhibits the mitochondrial respiration chain and induces ceramide channel formation and the closure of voltage-dependent anion channels, leading to mitochondrial dysfunction, altered Bcl-2 family protein expression, ROS generation and disturbed calcium homeostasis. This activates ceramide-induced signaling pathways, leading to apoptosis. These events are mitigated by S1P/S1P receptors (S1PRs) that restore mitochondrial function and activate signaling pathways. SphK1 promotes survival and cell proliferation and inhibits inflammation, while SphK2 has the opposite effect. However, both SphK1 and SphK2 promote fibrosis. Thus, a ceramide-SphKs/S1P rheostat modulates oxidant-induced kidney injury by affecting mitochondrial function, ROS production, Bcl-2 family proteins, calcium homeostasis and their downstream signaling pathways. This review will summarize the current evidence for a role of interaction between ROS-antioxidants and ceramide-SphKs/S1P and of a ceramide-SphKs/S1P rheostat in the regulation of oxidative stress-mediated kidney diseases.

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Section: Interaction Between Ros and S1p In Oxidant-induced Kidney In...mentioning

confidence: 99%

Section: Roles Of Mitochondria and Cell Signaling Pathways For S1p-in...mentioning

confidence: 99%

Section: A Rheostat Of Ceramide-s1p In the Regulation Of Oxidative St...mentioning

confidence: 99%

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A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Ueda

2022

IJMS

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“…Podocytes are highly differentiated cells on the lateral surface of the glomerular basement membrane and play an important role in maintaining the structure and function of the glomerular filtration barrier 66 . Podocyte dysfunction and loss because of apoptosis can contribute to massive proteinuria in DKD patients 67 , 68 . Various metabolites [e.g., advanced glycation end products (AGEs), uremic toxin, and methylglyoxal] can damage podocytes and lead to DKD 69 – 71 .…”

Section: Lysosomal Dysfunction and Enzyme Abnormalities Of Podocytes In Patients With Dkdmentioning

confidence: 99%

Relationship between lysosomal dyshomeostasis and progression of diabetic kidney disease

Zhang

et al. 2021

Cell Death Dis

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Lysosomes are organelles involved in cell metabolism, waste degradation, and cellular material circulation. They play a key role in the maintenance of cellular physiological homeostasis. Compared with the lysosomal content of other organs, that of the kidney is abundant, and lysosomal abnormalities are associated with the occurrence and development of certain renal diseases. Lysosomal structure and function in intrinsic renal cells are impaired in diabetic kidney disease (DKD). Promoting lysosomal biosynthesis and/or restoring lysosomal function can repair damaged podocytes and proximal tubular epithelial cells, and delay the progression of DKD. Lysosomal homeostasis maintenance may be advantageous in alleviating DKD. Here, we systematically reviewed the latest advances in the relationship between lysosomal dyshomeostasis and progression of DKD based on recent literature to further elucidate the mechanism of renal injury in diabetes mellitus and to highlight the application potential of lysosomal homeostasis maintenance as a new prevention and treatment strategy for DKD. However, research on screening effective interventions for lysosomal dyshomeostasis is still in its infancy, and thus should be the focus of future research studies. The screening out of cell-specific lysosomal function regulation targets according to the different stages of DKD, so as to realize the controllable targeted regulation of cell lysosomal function during DKD, is the key to the successful clinical development of this therapeutic strategy.

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“…The two S1P-generating enzymes, Sphk1 and Sphk2, seem to have opposite effects in mouse models of CKD, such as in diabetes-induced glomerulosclerosis and in unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis. While the depletion or inhibition of Sphk1 aggravated disease symptoms, depletion or inhibition of Sphk2 rather reduced disease symptoms [37][38][39][40][41][42][43]. Based on these data, it is tempting to speculate that the subcellular site of S1P production and/or action causes the difference in disease outcome.…”

Section: Introductionmentioning

confidence: 99%

S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P1 and S1P3 Receptor Activation and HIF-2α Stabilization

Hafizi

Imeri

Wenger

et al. 2021

IJMS

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Erythropoietin (Epo) is the critical hormone for erythropoiesis. In adults, Epo is mainly produced by a subset of interstitial fibroblasts in the kidney, with minor amounts being produced in the liver and the brain. In this study, we used the immortalized renal interstitial fibroblast cell line FAIK F3-5 to investigate the ability of the bioactive sphingolipid sphingosine 1-phosphate (S1P) to stimulate Epo production and to reveal the mechanism involved. Stimulation of cells with exogenous S1P under normoxic conditions (21% O2) led to a dose-dependent increase in Epo mRNA and protein levels and subsequent release of Epo into the medium. S1P also enhanced the stabilization of HIF-2α, a key transcription factor for Epo expression. S1P-stimulated Epo mRNA and protein expression was abolished by HIF-2α mRNA knockdown or by the HIF-2 inhibitor compound 2. Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P1 and S1P3 antagonists NIBR-0213 and TY-52156, but not by the S1P2 antagonist JTE-013. Moreover, inhibitors of the classical MAPK/ERK, the p38-MAPK, and inhibitors of protein kinase (PK) C and D all blocked the effect of S1P on Epo expression. Finally, the S1P and FTY720 effects were recapitulated in the Epo-producing human neuroblastoma cell line Kelly, suggesting that S1P receptor-dependent Epo synthesis is of general relevance and not species-specific. In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P1 and 3 receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs.

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Loss of sphingosine kinase 2 enhances Wilm's tumor suppressor gene 1 and nephrin expression in podocytes and protects from streptozotocin-induced podocytopathy and albuminuria in mice

Cited by 15 publications

References 70 publications

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Relationship between lysosomal dyshomeostasis and progression of diabetic kidney disease

S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P1 and S1P3 Receptor Activation and HIF-2α Stabilization

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