Abstract

The kidney is an important organ for maintaining Ca²⁺ homeostasis in the body. Nevertheless, disturbances in Ca²⁺ homeostasis can result in a range of renal diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), pleocytosis and diabetic nephropathy. During renal disease progression, Ca²⁺ signaling pathways play a key role in a variety of cellular activities such as cell necrosis, apoptosis, erythrocyte decay, and autophagy. Importantly, there are complex networks of Ca²⁺ fluxes between the endoplasmic reticulum (ER), mitochondria, and lysosomes that regulate Ca²⁺ signaling within renal cells and contribute to the development of renal disease. In addition, Ca²⁺ signaling links the interaction between various cell death and autophagy under heavy metal or high glucose stress. Therefore, this paper provides a review of the role of the Ca²⁺ signaling pathway in cell death, its interaction with autophagy, and its potential as a therapeutic target, with the aim of providing new and effective targets for the treatment of renal diseases.

Keywords: Ca2+ signaling; cell death; autophagy; kidney diseases; Cistanche extract

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Introduction

Through progressive evolutionary development, calcium has become one of the most important metallic elements in living organisms. The calcium ion (Ca²⁺) has a wide range of biological functions in living organisms and is involved in almost every process from birth to death.

Ca²⁺ is mainly stored in bone in the form of CaPO3 (hydroxyapatite), which plays a structural role in bone and can also be dissolved as a source of Ca²⁺ in the blood. In addition, Ca²⁺ is a ubiquitous and multifunctional signaling molecule that controls a wide range of life processes including muscle contraction, neuronal transmission, hormone secretion, organelle communication, cell movement, fertilization, and cell growth. Due to the critical role of Ca²⁺ in these life activities, intracellular Ca²⁺ concentrations are tightly regulated, and dysfunctional intracellular Ca²⁺ homeostasis is closely associated with many diseases such as heart and liver disease, aging, type 2 diabetes, and certain cancers.

Ca²⁺ homeostasis is essential for the maintenance of Ca²⁺ homeostasis in the body; Ca²⁺ signaling systems in renal cells regulate cellular processes and determine cell fate, including cell proliferation, apoptosis, necrosis, and autophagy, which are all associated with renal disease. dominant polycystic kidney disease (ADPKD), pleocytosis, diabetic nephropathy, and a range of other renal diseases have an impact on the development and progression of these diseases, as discussed below.

On the basis of the importance of Ca²⁺ signaling in regulating cell fate in the context of renal disease, this article provides a review of Ca²⁺ signaling-determined cell death in renal cells and erythrocytes. The role of Ca²⁺ signaling in renal disease and certain types of cell death regulated by Ca²⁺ signaling are reviewed. In addition, the targets of Ca²⁺ signaling pathways for the prevention of renal disease are discussed.

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The relationship between intracellular Ca²⁺ signaling and various forms of cell death in the kidney

Ca²⁺ not only modulates the normal life activities of cells and organisms but has been discovered to play an instrumental role in the modulation of many types of cell death. The early death of necrotic cells is correlated with intracellular Ca²⁺ overload. Apoptosis was also found to be regulated by Ca²⁺ signaling, and other cellular activities, including erythrocyte death (erythrocyte decay), were also shown to be regulated by Ca²⁺. In addition, Ca²⁺ signaling is an important mediator of autophagy and plays a dual role in cell survival and death. Numerous Ca²⁺ channels in the cell membrane, endoplasmic reticulum, and mitochondria, as well as alterations in lysosomes, regulate cytoplasmic Ca2+ levels associated with cell necrosis, apoptosis, erythrocyte decay, and autophagy. Under the terms "Ca²⁺", "kidney disease", "kidney injury", " necrosis", "apoptosis", "autophagy", "endoplasmic reticulum (ER )", "mitochondria", and "lysosome" were used as keywords to search the PubMed database for the original research literature of the last 20 years, and The articles were sorted by "best match" and "summary" format. For the review articles, we referred to the information mentioned in the study by Aromataris et al. such as the source and number of databases searched, the number of studies, the type and country of origin of the studies included in each review, and the synthesis/analysis method used to synthesize the evidence.

1. Ca²⁺ mediates renal injury necrosis

Necrosis is early cell death that is associated with intracellular Ca²⁺ overload and has been found to be regulated by intracellular Ca²⁺ release and/or extracellular Ca²⁺ inward flow. Methylglyoxal is a physiological glucose metabolite that induces necrotic cell death in canine renal tubular cells by stimulating extracellular Ca²⁺ inward flow and endoplasmic reticulum Ca²⁺ release. In isolated rabbit kidney cortical microsomes, the oxidant start-buty1 hydroperoxide (TBHP) caused endoplasmic reticulum lipid peroxidation and Ca²⁺ release, whereas the endoplasmic reticulum Ca²⁺ reuptake pump inhibitor toxic carotene reduced TBHP-induced necrotic cell death. In isolated perfused kidney and cultured renal tubular epithelial cells, white spiny snake venom increased cytoplasmic Ca²⁺ in a concentration-dependent manner and was mainly involved in cellular necrosis, leading to acute renal failure and nephrotoxicity. This suggests that intracellular Ca²⁺ release mediates stress-induced necrotizing cell death in renal cells.

Transient receptor potential anchor protein 1 (TRPA1), a redox-sensing Ca²⁺ endocytosis channel, is upregulated in renal tubules of patients with acute tubular necrosis and is significantly associated with a high incidence of recovery of renal function. Stone-forming calcium crystals such as calcium phosphate (CaP), calcium oxalate (CaOx), and CaP + CaOx enter renal tubular cells via endocytosis and promote necrosis through Ca²⁺ endocytosis (SOCE) operated by calcium pools, leading to prolonged Ca²⁺ endocytosis and resulting in persistently elevated intracellular Ca²⁺ levels. This suggests that in the porcine renal proximal tubule cell line LLC-PK1, stimulation of calcium-sensitive receptors (CaSR) by melamine leads to a sustained elevation of intracellular Ca²⁺ levels, resulting in enhanced ROS production and a dose-dependent increase in apoptotic and necroptotic cell death. However, l -ornithine activation of CaSR protects proximal tubular cells from h2o2-induced necrosis and attenuates subsequent acute kidney injury (AKI), which is mediated by transient receptor potential (TRPC)-dependent receptor-operated Ca²⁺ inward flow. Due to this nephroprotective effect of l -ornithine, it may be an effective treatment for reversing renal disease. These results suggest a dual role for Ca²⁺ inotropic channels mediating Ca²⁺ inward flow in renal epithelial cells. Sustained extracellular Ca²⁺ inward flow promotes renal cell necrosis, whereas regulation of appropriate extracellular Ca²⁺ inward flow protects against renal injury.

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In addition, Na+/Ca²⁺ exchange is one of the major factors in reversing intracellular Ca²⁺ overload in animals with ischemia/reperfusion injury and contrast-induced acute kidney injury.16,17 The Na+/Ca²⁺ exchange inhibitor KB-R7943 significantly attenuated renal injury and Ca²⁺ deposition in necrotic tubular epithelial cells, suggesting that KB-R7943 may be the use of Cyclophosphamide chemotherapy is limited by the nephrotoxicity caused by its metabolite, Chloroacetaldehyde. Chloroacetaldehyde induces a sustained elevation of intracellular free Ca²⁺ through inhibition of the Na+/Ca²⁺ exchanger, leading to necrotizing rather than apoptotic cell death and ultimately nephrotoxicity.18 Both KB-R7943 and Chloroacetaldehyde contribute to the inhibition of Na+-dependent intracellular Ca²⁺ extrusion; however, the former does not cause nephrotoxicity, which may be related to the different levels of intracellular Ca²⁺ loading in the kidney.

2. calcium signaling-mediated apoptosis contributes to kidney disease

Apoptosis, or autonomously programmed cell death, is an important process for maintaining the stability of the body's internal environment and helps the body to better adapt to its survival. In kidney injury, apoptosis usually accompanies necrosis, and Ca²⁺ signaling is an important regulator of apoptosis. In renal ischemia/reperfusion (I/R) injury, Ca²⁺ overload leads to necrotizing or apoptotic death. Sustained endoplasmic reticulum Ca²⁺ release induces endoplasmic reticulum stress and oxidative stress, leading to glomerular thylakoid apoptosis and participating in the progression of CKD. CaSR is a pleiotropic receptor capable of regulating Ca²⁺ homeostasis and plays an important role in renal cells and tumors. adipoRon activates the lipocalin receptor and Cynaracase activates CaSR to increase intracellular Ca²⁺ levels, thereby inhibiting high glucose-induced apoptosis in kidney cells and attenuating glomerular endothelial cell and podocyte injury in type 2 diabetes-related diabetic nephropathy. This suggests that regulation of intracellular Ca²⁺ can control apoptosis in renal cells.

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2.1. Endoplasmic reticulum (ER) Ca2+ signaling mediates apoptosis in renal disease

It is well known that the ER is the largest intracellular Ca2+ reservoir and plays an important role in regulating intracellular Ca2+ homeostasis; however, its dysregulation can lead to apoptosis. Endoplasmic reticulum Ca2+ homeostasis is mainly controlled by two Ca2+ release channels [inositol 1,4,5-trisphosphate receptor (IP3R) and eribulin receptor (RyR)] and one Ca2+ reuptake channel [sarcoplasmic/endoplasmic reticulum Ca2+- ATPase (SERCA)]. Dysfunction of these ER Ca2+ channels can cause a variety of renal diseases, including ischemia/reperfusion (I/R)-induced tubular injury, autosomal dominant polycystic kidney disease (ADPKD), pleocytosis, and diabetic nephropathy. It has been reported that when IP3R is activated, the beginning Ca2+ cascade of endoplasmic reticulum stores is released, thereby inducing renal tubular apoptosis.

Furthermore, inhibition of S2681 phosphorylation of IP3R1 increased ip3-induced intracellular Ca2+ release in cystic cells, which contributed to increased apoptosis in ADPKD cells. In endoplasmic reticulum-stressed podocytes, RyR2 phosphorylation at the S2808 site caused endoplasmic reticulum Ca2+ efflux via leaky RyR2, which in turn activated the cytoplasmic protease calpain 2, leading to podocyte injury and apoptosis. There is evidence that a significant reduction in renal SERCA2 activity and expression promotes the development of diabetic nephropathy through an endoplasmic reticulum stress-mediated apoptotic pathway. These results suggest that endoplasmic reticulum Ca2+ channels play an important role in maintaining intracellular Ca2+ homeostasis in the kidney, and therefore, renal apoptosis and renal dysfunction are important contributors to the development of renal disease.

2.2. ER-Mitochondrial Ca2+ Signaling Mediates Apoptosis in Kidney Disease

mitochondria represent another intracellular Ca2+ store, and Ca2+ signaling mediates the interaction between the endoplasmic reticulum and mitochondria. the Ca2+ released by IP3R in response to endoplasmic reticulum stress is sequestered by mitochondria for mitochondrial respiration and ATP production and regulates cell survival. Mitochondrial release of calpain or caspase-3 promotes alterations in ER Ca2+ channels, including IP3R cleavage or RyR2 oxidation. These changes can significantly increase mitochondrial and cytoplasmic Ca2+ levels and increase apoptosis. In addition, cytochrome c released from mitochondria binds to IP3R, thereby blocking its functional inhibition and increasing cytoplasmic Ca2+ concentrations. sustained increases in Ca2+ levels counteract the release of cytochrome c and amplification of apoptotic signals. Endoplasmic reticulum-mitochondrial Ca2+ signaling plays a key role in the increased apoptosis found in renal disease. In diabetic nephropathy mice, impaired SERCA2 activity and expression leads to ER Ca2+ depletion, which triggers a mitochondria-mediated apoptotic pathway. Downregulation of the mitochondrial Ca2+ channel polycystin 2 enhances the expression of the endoplasmic reticulum-mitochondrial tethering protein mitochondrial fusion protein 2, which increases endoplasmic reticulum-mediated mitochondrial Ca2+ transport and apoptosis, thereby promoting ADPKD. In bilaterally I/R-injured kidneys, the endoplasmic reticulum protein sigma-1 receptor (Sig-1R) dissociated from BiP and bound to the endoplasmic reticulum Ca2+ release channel IP3R3 at the endoplasmic reticulum-mitochondria contact site, while stable IP3R3 prolonged Ca2+ signaling to mitochondria and promoted apoptosis. These results suggest that a complex Ca2+-regulated signaling pathway exists between the endoplasmic reticulum and mitochondria that are associated with apoptosis and plays an important role in renal disease.

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