3. Calcium-mediated erythrocyte decay in renal injury

Erythrocyte apoptosis, also known as erythrocyte suicide death, is characterized by cell shrinkage and exposure to phosphatidylserine (PS) on the erythrocyte surface. The cryptic cells are phagocytosed and thus rapidly cleared from the circulating blood. Erythrocyte apoptosis is the key event causing CKD-associated renal anemia and end-stage renal disease anemia. The fungal toxin ochratoxin A is known to be the causative agent of endemic Balkan nephropathy, which triggers anemia through Ca²⁺ entry into cells and increased cytoplasmic Ca²⁺ levels, leading to cellular suicide death or erythrocyte death. In addition, the uremic toxin indophenol sulfate induces erythrocyte suicide death by stimulating extracellular Ca²⁺ inward flow, which may contribute to anemia in end-stage renal disease. Vanadate VO4 3 -toxicity in the kidney also induced erythrocyte death by increasing cytoplasmic Ca²⁺ levels, which may have contributed to the development of anemia in chronic renal failure. In mice, a vitamin D-enriched diet enhanced stimulation of PS exposure and cellular contraction without significantly altering Ca²⁺ concentrations in freshly extracted erythrocytes, suggesting that the effects of vitamin D treatment may be ineffective in stimulating Ca²⁺ entry. These studies suggest that high Ca²⁺ entry or increased intracellular Ca²⁺ levels can promote erythrocyte apoptosis, which can lead to renal disease.

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4. Ca²⁺ Signaling Regulates Autophagy in Kidney Diseases

Macroautophagy/autophagy is an evolutionarily conserved process in eukaryotes and plays an important role in intracellular material recycling. During autophagy, some damaged organelles and harmful proteins are wrapped by autophagosomes in a bilayer membrane structure and then sent to lysosomes or vesicles for degradation and reuse. Ca²⁺, an important messenger molecule regulating cell death, is also involved in the regulation of autophagy.

It has been shown that intracellular Ca²⁺ signaling mediates autophagy in renal tubular cells. In vivo studies have shown that mTOR, a key regulator of the autophagic pathway, is involved in renal tubular repair after AKI. In conditionally immortalized proximal tubular epithelial cells (ciPTEC) generated from patients with ADPKD1, activation of CaSR increased intracellular Ca²⁺ release and decreased mTOR activity. Increased Ca²⁺ inward flow from renal proximal tubule cells inhibited mTOR-dependent autophagy, thereby making cells more susceptible to death. This suggests that mTOR-dependent autophagy, regulated by intracellular Ca²⁺ release or Ca²⁺ inward flow, controls the development of renal disease.

The classical transient receptor potential channel 6 (TRPC6) is the major intracellular Ca²⁺ inward flow channel in the kidney and plays an important role in renal diseases such as diabetic nephropathy, immune-mediated renal disease, renal fibrosis, glomerular disease, and CKD. In vitro studies on renal proximal tubular cells have shown that trpc6-mediated Ca2+ inward flow inhibits the cytoprotective effects of autophagy. The same study showed that trpc6 knockdown promoted autophagic flow and attenuated tubular cell apoptosis during renal I/R, which is the main cause of AKI. The transient receptor potential non-selective cation channel, subfamily M, member 3 (TRPM3) is another Ca2+ channel that mediates Ca²⁺ flow to regulate autophagy. increased expression leads to Ca²⁺ influx and stimulates autophagy via the CAMKK2/AMPK/ULK1 pathway, promoting the growth of renal clear cell carcinoma (ccRCC). These results suggest that Ca²⁺ channels in the cell membrane mediate Ca²⁺ inward flow and inhibit autophagy and may play a role in kidney injury or disease.

In addition, intracellular Ca²⁺ regulators can mediate autophagy and play an important role in renal disease. Stromal interaction molecule 1 (STIM1), a key regulator of endoplasmic reticulum Ca²⁺, activates store-operated Ca²⁺ entry (SOCE) in response to perceived endoplasmic reticulum Ca²⁺ depletion. In serum-cultured podocytes from rats with diabetic nephropathy, silencing STIM1 reversed reduced autophagy and increased epithelial-mesenchymal transition (EMT) by restoring Ca²⁺ homeostasis. In podocytes with ADPKD, cystic kidneys have defective autophagy and enhanced EMT, which can be reversed by silencing high levels of STIM1 by reducing ER Ca²⁺ release. In renal epithelial cells from patients with ADPKD, autophagy is inhibited due to a lack of interaction between BECN1 and PKD2, a mutant encoding polycystin 2 (PC2), which prolongs the increase in intracellular Ca²⁺ levels. The APOL1 variant exacerbates renal inflammation by antagonizing the Ca²⁺-dependent binding of APOL3 to neuronal calcium sensor 1 (NCS-1) and by interfering with the autophagy of podocytes through interaction with pi4-kinase IIIb. The role of these intracellular Ca²⁺ regulators suggests that a complex network of intracellular Ca²⁺-regulated autophagy also exists in renal disease.

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5. Lysosomal Ca²⁺ signaling in kidney disease

Lysosomal Ca²⁺ contributes to autophagy and is important for lysosomal degradation. Lysosomal degradation is mediated by calcium-activated proteases calpains (CAPNs) on lysosomes. lack of PKD1 impairs lysosomal acidification in a CAPN protease-dependent manner, and inactivating mutations in PKD1 or PKD2 lead to ADPKD. However, lysosomal Ca²⁺ stores are not affected in cystinosis ciPTEC cell lines, and some extracellular agonist-induced Ca²⁺ responses may be involved in the pathogenesis of the disease. Therefore, whether lysosomal Ca²⁺ signaling is involved in the development of renal disease also depends on the type of renal cells.

In addition, the distribution of intracellular Ca²⁺ between the ER, mitochondria, and lysosomes may affect the degradation function of lysosomes. Mitochondria contact the endoplasmic reticulum membrane via the mitochondrial-associated membrane (MAM), which provides communication between these two organelles and mediates Ca²⁺ transfer from the endoplasmic reticulum to the mitochondria. In addition, mam-mediated endoplasmic reticulum-mitochondrial Ca²⁺ crosstalk regulates apoptosis and autophagy and is involved in the pathogenesis of the renal disease. It was shown that Ca²⁺ redistribution from the endoplasmic reticulum to mitochondria regulated apoptosis and autophagy and promoted lead-induced nephrotoxicity in primary rat proximal renal tubular cells. With the Ca²⁺ release channel IP3R and Ca²⁺ reuptake pump SERCA, the endoplasmic reticulum delivers cytoplasmic Ca²⁺ to lysosomes in a "histone-like" manner. The lysosomal acidic environment is mainly regulated by the lysosomal v-ATPase and is thought to be regulated by Ca²⁺ /H+ exchange, although such regulation has not been found in mammalian cells. In hepatocyte HepG2, Cd induces Ca²⁺ release from the endoplasmic reticulum pool into the cytoplasm, thereby disrupting the lysosomal acidic environment and leading to its degradation. However, the cd-disrupted lysosomal pH was restored by pretreatment with the IP3R inhibitor 2-APB and the SERCA activator CDN1163. This suggests that Ca²⁺ mediates the interactions between the endoplasmic reticulum, mitochondria, and lysosomes and regulates lysosomal function.

It has also been proposed that Ca²⁺ efflux from the ER regulates lysosomal Ca²⁺ levels. The endoplasmic reticulum Ca²⁺ channel-like protein transmembrane BAX inhibitory motif 6 (TMBIM6) not only mediates the endoplasmic reticulum stress response and apoptosis but also regulates the local release of Ca²⁺through lysosomal transient receptor potential mucin 1 (TRPML1) channels, triggering the induction of autophagy in the kidney of starved mice. In addition, lysosomal TRPML1 regulates mitochondrial-lysosomal contacts and facilitates Ca²⁺ transfer from lysosomes to mitochondria, thereby regulating mitochondrial homeostasis. In addition, TRPML1-mediated lysosomal Ca²⁺ release regulates transcription factor EB (TFEB), which regulates TRPML1 expression at the transcriptional level, as well as the expression of other autophagy and lysosomal genes. In primary proximal renal tubular cells, Cd induces lysosomal dysfunction through TFEB-dependent lysosomal degradation, leading to sustained activation of Nrf2 and resulting in renal injury. Furthermore, in a study of a podocyte-specific knockout mouse (Asah1fl/fl/PodoCre) deficient in the alpha subunit of acid ceramidase, lysosomal Ca²⁺ release via TRPML1 channels was inhibited in podocytes, which may be associated with the development of pleocytosis and related nephrotic syndromes. These results suggest that lysosomal Ca²⁺ is regulated in the intracellular Ca²⁺ storage system and may play an important role in the progression of renal disease.

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Ca²⁺ signaling is associated with renal cell death and autophagy

The relationship between cell death and autophagy is complex and sometimes contradictory, but it is crucial for cell fate. Interestingly, Ca²⁺ signaling acts as a bridge between these two cellular activities. Ca²⁺ promotes cell proliferation and survival by releasing IP3R through the endoplasmic reticulum; Ca²⁺ is then transferred to the mitochondria to activate mitochondrial metabolism. Impaired mitochondrial Ca²⁺ homeostasis leads to mitochondrial autophagic degradation through the activation of AMPK. Mitochondrial Ca²⁺ overload leads to the production of reactive oxygen species (ROS) and the release of cytochrome c, which ultimately leads to apoptosis. Therefore, Ca²⁺ signaling and Ca²⁺ subcellular homeostasis may determine the balance between cell survival, apoptosis, and autophagy

1. Induced autophagy promotes cell death

In some cases, induced autophagy promotes cell death. In a unilateral ureteral obstruction (UUO) mouse model of renal fibrosis, autophagy persisted in the proximal renal tubules. Pharmacological inhibition of autophagy and proximal renal tubule-specific knockdown of autophagy-associated protein 7 (PT-ATG7 KO) inhibited tubular atrophy, apoptosis, renal unit loss, and interstitial macrophage infiltration in these mice. This suggests that sustained autophagy induced in the renal proximal tubule during UUO promotes interstitial fibrosis. In addition, extracellular Ca²⁺ inward flow triggered by the antimicrobial peptide Trichokonin VI induced autophagy and apoptosis in hepatocellular carcinoma cells. In addition, siRNA knockdown of the autophagy-associated gene (ATG5) reduced apoptosis. This suggests that Cd induces autophagic cell death of mitochondrial origin in hepatocytes in a dose-dependent manner. Melatonin is hepatoprotective in cd-exposed mice by inhibiting cd-induced autophagic cell death. In mouse spleen and human B cells, Cd promoted apoptosis by upregulating intracellular Ca²⁺-induced vacuole membrane protein 1 (VMP1)-mediated autophagy. In RAW264.7 mouse monocytes, cadmium-induced autophagy and er-mediated apoptosis; however, pharmacological and genetic inhibition of autophagy inhibited cd-induced apoptosis.

Furthermore, the Ca²⁺ chelator completely restored cell viability and inhibited cd-induced apoptosis and autophagy. In porcine kidney cells LLC-PK1, autophagy mediator calpain induced cell necrosis before apoptosis by increasing intracellular Ca²⁺ levels under high glucose conditions. In addition, Ca²⁺ plays an important role in iron death, an autophagy-dependent cell death that has recently been shown to have relevance in a variety of renal diseases. These studies suggest that intracellular Ca²⁺ signaling-mediated autophagy may promote cell death and be associated with renal disease.

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2. Inhibition of autophagy promotes cell death

In some cases, induced autophagy has a protective effect against cell death. It was shown that high glucose promotes autophagic flow in podocyte cultures and induces LC3BII expression in diabetic mouse podocytes. Specifically, the deletion of ATG5 in podocytes resulted in accelerated diabetes-induced pleocytosis with leakage of the glomerular filtration barrier and glomerulosclerosis. In addition, endothelial-specific ATG5 deficiency also leads to capillary thinning and accelerated diabetic nephropathy. Thus, endothelial and podocyte autophagy synergistically protect against diabetes-induced glomerulosclerosis. In mouse glomerular thylakoid cells (MES-13), Cd-induced ER Ca2+ release via IP3R, induced autophagy and apoptosis. In addition, Cd induced the expression of LC3B-II but reduced the expression of sequestosome-1 (p62) in rat thylakoid cells. When autophagy was disrupted by knockdown or RNA silencing, cell viability was reduced and increased pro-caspase-3 cleavage indicated the onset of apoptosis. These results suggest that induced autophagy protects against nephrotoxicity.

However, the initial autophagic protection is transformed into the disruption of autophagic flow, leading to cell death in renal cells. In other words, inhibition of autophagy leads to cell death. The autophagy inhibitor 3-methyladenine exacerbates cd-induced germ cell apoptosis, whereas the autophagy inducer rapamycin attenuates this effect. More importantly, the deletion of ATG5 in supporting cells exacerbated cd-triggered germ cell apoptosis. This suggests that autophagy of Sertoli cells prevents cd-induced apoptosis in mouse testicular germ cells. Activation of autophagy has also been shown to inhibit cd-triggered apoptosis in the human placental trophectoderm and mouse placenta. The kidney, as an important excretory organ, is a major target for the accumulation of toxins such as heavy metals. Previous studies have shown that cadmium induces kidney injury and apoptosis through long-term inhibition of autophagic flow. In vitro studies have also shown that inhibition of autophagic flow can exacerbate apoptosis; the Ca²⁺ signaling pathway may link these two cellular activities. In mouse renal tubular cells, cd-inhibited autophagic flow exacerbated apoptosis by inducing elevated Ca²⁺ levels. In primary rat proximal tubular cells, cadmium and lead (Pb)-inhibited autophagic degradation exacerbated apoptotic death, possibly due to redistribution of subcellular Ca²⁺ between the ER, cytoplasm, and mitochondria. activation of CaSR could promote cell proliferation and protect against cd-induced apoptosis in renal tubular cells by competing for PLC-IP3-Ca²⁺ signaling. Restoration of Ca²⁺-mediated autophagic processes could protect against heavy metal-induced renal cytotoxicity and kidney injury. It is suggested that inhibition of autophagy mediated by elevated intracellular Ca²⁺ levels may exacerbate the involvement of apoptosis in renal injury

Conclusions

In summary, the kidney plays a key role in regulating Ca2+ homeostasis in vivo; therefore, disruption of Ca2+ homeostasis will cause a series of renal diseases. The regulation of Ca2+ signaling in renal cells determines cell fate and is closely related to renal diseases. Ca2+ microstructural domains, including the endoplasmic reticulum, mitochondria, and lysosomes, regulate various modes of cell death, such as necrosis, apoptosis, and erythrocyte decay, and when these modes of death are disrupted, they lead to the overall development of renal disease. In addition, interactions between Ca2+ microdomains mediate the interaction between these forms of cell death and autophagy. Based on the role of Ca2+ microstructural domains in regulating kidney cell fate, targeting these Ca2+ signals may lead to novel strategies for treating kidney disease.

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