Regucalcin in proximal tubule epithelial kidney cells (WP4838)

Homo sapiens

This pathway includes the proximal tubule epithelial kidney cells (NRK52E cell) with a basolateral and apical side and other schematic illustrated organelles involved in the process of kidney function. The influence of regucalcin on the intra-and extracellular Ca2+ regulation is showed which are both involved in cell proliferation, ion transport and apoptosis and are important in normal kidney function. When the regulation of regucalcin and other factors are downregulated and suppressed the kidney fails in functionality and so renal fibrosis will develop. First of all, TNF-B and TNF-a do have an impact on the activity of Smad which has an impact on the development of a-SMA that induced renal fibrosis. NF-kB, stimulated by TNF-a, activates the transcription factor p65 that induced the IL-8 expression which is involved in inflammatory pathways. On the other hand, regucalcin inhibits the a-SMA which means that the formation of renal fibrosis is inhibited. Further, TNF-B stimulates the caspase 8 that activates the cytochrome C which activate the apoptosis pathway. Also, here regucalcin function as an inhibitor for Apaf1 that results in an inhibition of the apoptosis pathway and activate the Bcl-2 (suppressor of apoptotic cell death). Besides the TNF-B and TNF-a pathway, there is an RTK pathway illustrated which activates the PI3K and RAS pathway for stimulation of the protein and cell proliferation. According to Yamaguchi M. (2015), regucalcin activates the Akt1 to induce the protein proliferation even further when PI3K is inhibited. The RTK pathway shows interaction with the cAMP pathway that stimulate the protein kinase A and the PIP2 pathway that stimulate the protein kinase C and IP3. These all will stimulate Ca2+ release from the endoplasmic reticulum (ER). This Ca2+ can migrate and enters the mitochondria through the Ca2+ uniporter which results in the activation of mitochondrial biological processes or release of different mitochondrial factors. Hence, calcium controls and modulate cell apoptosis and inflammation. MAP3K pathway might be involved in the stimulation of RAF1 to induce the cell proliferation and the increase in apoptosis by inhibition of Bcl-2 through JNK which is also activated by ROS. Ca2+ released by the ER can also bind to calmodulin to form the Ca2+/calmodulin complex that stimulates IP3, JNK, NOS, RGPR—p117 and NF1. The latter two proteins are involved in the enhancement of regucalcin gene expression. On the other hand, regucalcin can inhibit the activity of Ca2+/calmodulin complex and the NOS. Normally, phosphodiesterase binds cAMP that induced the degradation of cAMP which results in a decrease of protein kinase A that leads to a reduction of ER Ca2+ release. Regucalcin inhibits the phosphodiesterase in such a way that cAMP will not be degraded and the ER Ca2+ release can further occur. Remaining Ca2+ released from the ER can also transport to the microsomes, enters vis Ca2+ uniporter, to induce microsomal activities. This process of microsomal Ca2+ uptake can be diminished through the inhibition of IP3 kinase. Regucalcin is not only involved in the regulation of intracellular Ca2+ release or uptake, but also extracellular Ca2+ by stimulating the Ca2+/ATPase which leads to Ca2+ export. Besides that, the Na+/Ca2+ exchanger is important to be present on the basolateral membrane of the proximal tubule epithelial kidney cell to regulate the ion transport. On the apical membrane is the TRPV5 receptor present that regulate the import of Ca2+ from the lumen back into the kidney cell, but Ca2+ can also travel via paracellular transport. Further, in the nucleus the regucalcin has an influence on the inhibition of the serine/threonine phosphate (PSP), tyrosine phosphatase (PTP) and calcineurin gene expression. Normally, PSP stimulates the protein kinase A- and so the ER Ca2+ release-, PTP stimulates the cell growth and differentiation and calcineurin will migrate to the cytoplasm for binding to the Ca2+ and stimulates the formation of Ca2+/calmodulin complex. In general, regucalcin regulates the factors and proteins involved in ion transport, cell proliferation and apoptosis.

Authors

Pip van Lier , Friederike Ehrhart , Egon Willighagen , Martina Summer-Kutmon , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Annotations

Disease Ontology

kidney failure kidney disease

Cell Type Ontology

kidney cell

Pathway Ontology

regulatory pathway signaling pathway

Participants

Label Type Compact URI Comment
PMA Metabolite chebi:37537
ROS Metabolite chebi:26523
Trifluoperazine Metabolite chebi:45951
IP3 Metabolite chebi:16595
MEK Metabolite chebi:28398
PSP Metabolite chebi:31991
cAMP Metabolite chebi:17489
DAG Metabolite chebi:41847
AMP Metabolite chebi:16027
Nitric oxide signaling Metabolite chebi:16480
PTP Metabolite chebi:52242
PIP2 Metabolite chebi:18348
NO Metabolite chebi:16480
Aldosterone Metabolite chebi:27584
Bcl-2 Metabolite chebi:133022
Calmodulin Metabolite chebi:3324
Lanthanum chloride Metabolite wikidata:Q421212
L-arginine Metabolite chebi:32682
Cytochrome C Metabolite chebi:18070
Ruthenium red Metabolite chebi:34956
3Na+ Metabolite chebi:29101
Diacylglycerol Metabolite chebi:18035
Ca2+ Metabolite chebi:29108
ROS Metabolite chebi:70982
BAX GeneProduct ensembl:ENSG00000087088
PTH GeneProduct ensembl:ENSG00000152266
TRPV5 GeneProduct ensembl:ENSG00000127412
SMAD2 GeneProduct ensembl:ENSG00000175387
SMAD4 GeneProduct ensembl:ENSG00000141646
MAPK1 GeneProduct ensembl:ENSG00000100030
MTOR GeneProduct ensembl:ENSG00000198793
TGFB1 GeneProduct ensembl:ENSG00000105329
AKT1 GeneProduct ensembl:ENSG00000142208
TNFRSF1A GeneProduct ensembl:ENSG00000067182
BAK1 GeneProduct ensembl:ENSG00000030110
ACTA2 GeneProduct ensembl:ENSG00000107796
APAF1 GeneProduct ensembl:ENSG00000120868
BRAF GeneProduct ensembl:ENSG00000157764
RAF1 GeneProduct ensembl:ENSG00000132155
PI3K3CA Protein ensembl:ENSG00000121879
TNFSF11 Protein ensembl:ENSG00000120659
CASP8 Protein ensembl:ENSG00000064012
PPP3R1 Protein ensembl:ENSG00000221823
CASP9 Protein ensembl:ENSG00000132906
RELA Protein uniprot:A0A087WVP0
TNFA Protein uniprot:P16599
TGFBR1 Protein uniprot:P36897
SENP8 Protein uniprot:KW-0788
RGN Protein uniprot:Q15493
SLC8A1 Protein uniprot:Q01728
CASP3 Protein uniprot:P42574
PRKCQ Protein uniprot:A0A087X0I9
FFAR3 Protein uniprot:A0A0K0PUW7
NF1 Protein uniprot:P97526
NR3C2 Protein uniprot:P22199
NOS1 Protein uniprot:B3VK56
MAP3K5 Protein uniprot:Q99683
G3BP1 Protein uniprot:Q5U0Q1
CALCA Protein uniprot:P01258
PDE1B Protein uniprot:A0A024RB59
SEC16B Protein uniprot:Q96JE7
MAPK10 Protein uniprot:P49187
MAP2K1 Protein uniprot:Q01986
MAPK3 Protein uniprot:P21708
MCU Protein uniprot:Q8NE86
PRKACA Protein uniprot:P27791
ATP2B3 Protein uniprot:Q64568
ROS1 Protein uniprot:Q63132
Cytoplasmic mineralocorticoid receptor Protein uniprot:P22199
RGN Protein uniprot:Q15493

References

  1. Calcineurin regulatory subunit B is a unique calcium sensor that regulates calcineurin in both calcium-dependent and calcium-independent manner. Li J, Jia Z, Zhou W, Wei Q. Proteins. 2009 Nov 15;77(3):612–23. PubMed Europe PMC Scholia
  2. The potential role of regucalcin in kidney cell regulation: Involvement in renal failure (Review). Yamaguchi M. Int J Mol Med. 2015 Nov;36(5):1191–9. PubMed Europe PMC Scholia
  3. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Fantus D, Rogers NM, Grahammer F, Huber TB, Thomson AW. Nat Rev Nephrol. 2016 Oct;12(10):587–609. PubMed Europe PMC Scholia