Acidosis promotes cell apoptosis through the G protein‑coupled receptor 4/CCAAT/enhancer‑binding protein homologous protein pathway

Dong,Biao; Zhang,Xiaolu; Fan,Yafeng; Cao,Songqiang; Zhang,Xuepei

doi:10.3892/ol.2018.9478

Acidosis promotes cell apoptosis through the G protein‑coupled receptor 4/CCAAT/enhancer‑binding protein homologous protein pathway

Authors:
- Biao Dong
- Xiaolu Zhang
- Yafeng Fan
- Songqiang Cao
- Xuepei Zhang
View Affiliations

Affiliations: Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, P.R. China, Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Published online on: September 21, 2018 https://doi.org/10.3892/ol.2018.9478
Pages: 6735-6741

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the effects of acidosis on the apoptosis of renal epithelial and endothelial cells, and the molecular pathways responsible for this. A human proximal tubular cell line, HK‑2, and human umbilical vein endothelial cells (HUVECs), were transfected with control or G protein‑coupled receptor 4 siRNA for 36 h. Cells were exposed to normal (pH 7.4) or acidic (pH 6.4) media. Western blot analysis was used to assess the protein expression levels of G protein‑coupled receptor 4 (GPR4), CCAAT/enhancer‑binding protein homologous protein (CHOP) and cleaved caspase‑3. Cell apoptosis was examined using the TUNEL assay and the lactate dehydrogenase (LDH) release assay. Using these techniques, it was demonstrated that acidosis increased the protein expression levels of GPR4, CHOP, cleaved caspase‑3 and intracellular cyclic adenosine monophosphate levels in hypoxia/reoxygenation (HR)‑treated cell lines. Knockdown of GPR4 in HK‑2 cells and HUVECs markedly reduced the protein expression levels of acidosis‑mediated GPR4, CHOP and cleaved caspase‑3, as well as the rate of cell apoptosis. Therefore, the results of the present study suggested that acidosis promotes the apoptosis of HK‑2 cells and HUVECs by regulating the GPR4/CHOP pathway.

View Figures

View References

1	Koul PB: Diabetic ketoacidosis: A current appraisal of pathophysiology and management. Clin Pediatr (Phila). 48:135–144. 2009. View Article : Google Scholar : PubMed/NCBI
2	Poschet J, Perkett E and Deretic V: Hyperacidification in cystic fibrosis: Links with lung disease and new prospects for treatment. Trends Mol Med. 8:512–519. 2002. View Article : Google Scholar : PubMed/NCBI
3	Chen A, Dong L, Leffler NR, Asch AS, Witte ON and Yang LV: Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP/Epac pathway. PLoS One. 6:e275862011. View Article : Google Scholar : PubMed/NCBI
4	Bonventre JV: Mediators of ischemic renal injury. Annu Rev Med. 39:531–544. 1988. View Article : Google Scholar : PubMed/NCBI
5	Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, MacDonald JF, Wemmie JA, Price MP, Welsh MJ and Simon RP: Neuroprotection in Ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell. 118:687–698. 2004. View Article : Google Scholar : PubMed/NCBI
6	Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB and Petrovic S: Deletion of the pH sensor GPR4 decreases renal acid excretion. J Am Soc Nephrol. 21:1745–1755. 2010. View Article : Google Scholar : PubMed/NCBI
7	Brown D, Breton S, Ausiello DA and Marshansky V: Sensing, signaling and sorting events in kidney epithelial cell physiology. Traffic. 10:275–284. 2009. View Article : Google Scholar : PubMed/NCBI
8	Nishitoh H: CHOP is a multifunctional transcription factor in the ER stress response. J Biochem. 151:217–219. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tamaki N, Hatano E, Taura K, Tada M, Kodama Y, Nitta T, Iwaisako K, Seo S, Nakajima A, Ikai I and Uemoto S: CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol. 294:G498–G505. 2008. View Article : Google Scholar : PubMed/NCBI
10	Prachasilchai W, Sonoda H, Yokota-Ikeda N, Ito K, Kudo T, Imaizumi K and Ikeda M: The protective effect of a newly developed molecular chaperone-inducer against mouse ischemic acute kidney injury. J Pharmacol Sci. 109:311–314. 2009. View Article : Google Scholar : PubMed/NCBI
11	Dong L, Li Z, Leffler NR, Asch AS, Chi JT and Yang LV: Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLoS One. 8:e619912013. View Article : Google Scholar : PubMed/NCBI
12	Dong B, Zhou H, Han C, Yao J, Xu L, Zhang M, Fu Y and Xia Q: Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: The role of acidosis and GPR4. PLoS One. 9:e1109442014. View Article : Google Scholar : PubMed/NCBI
13	He K, Chen X, Han C, Xu L, Zhang J, Zhang M and Xia Q: Lipopolysaccharide-induced cross-tolerance against renal ischemia-reperfusion injury is mediated by hypoxia-inducible factor-2α-regulated nitric oxide production. Kidney Int. 85:276–288. 2014. View Article : Google Scholar : PubMed/NCBI
14	Miao J, Lesher AM, Miwa T, Sato S, Gullipalli D and Song WC: Tissue-specific deletion of Crry from mouse proximal tubular epithelial cells increases susceptibility to renal ischemia-reperfusion injury. Kidney Int. 86:726–737. 2014. View Article : Google Scholar : PubMed/NCBI
15	Yang LV, Radu CG, Roy M, Lee S, McLaughlin J, Teitell MA, Iruela-Arispe ML and Witte ON: Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol. 27:1334–1347. 2007. View Article : Google Scholar : PubMed/NCBI
16	Wang YC, Li WZ, Wu Y, Yin YY, Dong LY, Chen ZW and Wu WN: Acid-sensing ion channel 1a contributes to the effect of extracellular acidosis on NLRP1 inflammasome activation in cortical neurons. J Neuroinflammation. 12:2462015. View Article : Google Scholar : PubMed/NCBI
17	Cronberg T, Rytter A, Asztély F, Söder A and Wieloch T: Glucose but not lactate in combination with acidosis aggravates ischemic neuronal death in vitro. Stroke. 35:753–757. 2004. View Article : Google Scholar : PubMed/NCBI
18	Magalhães PA, Magalhães PA, de Brito TS, Freire RS, da Silva MT, dos Santos AA, Vale ML, de Menezes DB, Martins AM and Libório AB: Metabolic acidosis aggravates experimental acute kidney injury. Life Sci. 146:58–65. 2016. View Article : Google Scholar : PubMed/NCBI
19	Sanderlin E, Justus C, Krewson E and Yang L: Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress. Cell Health Cytoskelet. 2015:99–109. 2015.
20	Huang Y and McNamara JO: Ischemic stroke: ‘Acidotoxicity’ is a perpetrator. Cell. 118:665–666. 2004. View Article : Google Scholar : PubMed/NCBI
21	Dong L, Krewson EA and Yang LV: Acidosis activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. Int J Mol Sci. 18:pii: E2782017. View Article : Google Scholar
22	Ding X, Ma M, Teng J, Shao F, Wu E and Wang X: Numb protects human renal tubular epithelial cells from bovine serum albumin-induced apoptosis through antagonizing CHOP/PERK pathway. J Cell Biochem. 117:163–171. 2016. View Article : Google Scholar : PubMed/NCBI
23	Yang JR, Yao FH, Zhang JG, Ji ZY, Li KL, Zhan J, Tong YN, Lin LR and He YN: Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. Am J Physiol Renal Physiol. 306:F75–F84. 2014. View Article : Google Scholar : PubMed/NCBI
24	Nicol X, Hong KP and Spitzer NC: Spatial and temporal second messenger codes for growth cone turning. Proc Natl Acad Sci USA. 108:13776–13781. 2011. View Article : Google Scholar : PubMed/NCBI