Regucalcin in proximal tubule epithelial kidney cells (Homo sapiens)

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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, TGF-B (TGFB1) and TNF-a (TNFA) do have an impact on the activity of SMAD2/4 which has an impact on the development of a-SMA (ACTA2) that induced renal fibrosis. NF-kB (TNFSF11), stimulated by TNF-a, activates the transcription factor p65 (RELA) 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, TGF-B stimulates the caspase 8 (CASP8) 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 TGF-B and TNF-a pathway, there is an RTK pathway illustrated which activates the PI3K (PI3K3CA) and RAS (G3BP1) pathway for stimulation of the renal homeostasis, autophagy, protein and cell proliferation. According to Yamaguchi M. (2015), regucalcin activates the AKT1 to induce the renal homeostasis, autophagy and protein proliferation even further when PI3K is inhibited. The RTK pathway shows interaction with the cAMP pathway that stimulate the protein kinase A (PRKACA) and the PIP2 pathway that stimulate the protein kinase C (PRKCQ) 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 (MCU) 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 (MAPK10) 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 (SEC16B) 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 (PDE1B) 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 (ATP2B3) which leads to Ca2+ export. Besides that, the Na+/Ca2+ exchanger (SLC8A1) 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 (PPP3R1) 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. Research is done on rats.