Endoplasmic reticulum stress is involved in podocyte apoptosis induced by saturated fatty acid palmitate
- Author:
- No author available
- Journal Title:
- Chinese Medical Journal
- Issue:
- 17
- DOI:
- 10.3760/cma.j.issn.0366-6999.2012.17.031
- Key Word:
- diabetic nephropathy;endoplasmic reticulum stress;free fatty acid;podocyte;proteinuria
Abstract： Background Podocyte apoptosis is recently indicated as an early phenomenon of diabetic nephropathy.Pancreatic β-cells exposed to saturated free fatty acid palmitate undergo irreversible endoplasmic reticulum (ER) stress and consequent apoptosis,contributing to the onset of diabetes.We hypothesized that palmitate could induce podocyte apoptosis via ER stress,which initiates or aggravates proteinuria in diabetic nephropathy.Methods Podocyte apoptosis was detected by 4',6-diamidio-2-phenylindole (DAPI) stained apoptotic cell count and Annexin V-PI stain.The expressions of ER molecule chaperone glucose-regulated protein 78 (GRP78),indicators of ER-associated apoptosis C/EBP homologous protein (CHOP),and Bcl-2 were assayed by Western blotting and real-time PCR.GRP78 and synaptopodin were co-localized by immunofluorescence stain.Results Palmitate significantly increased the percentage of cultured apoptotic murine podocytes time-dependently when loading 0.75 mmol/L (10 hours,13 hours,and 15 hours compared with 0 hour,P ＜0.001) and dose-dependently when loading palmitate ranging from 0.25 to 1.00 mmol/L for 15 hours (compared to control,P ＜0.001).Palmitate time-dependently and dose-dependently increased the protein expression of GRP78 and CHOP,and decreased that of Bcl-2.Palmitate loading ranging from 0.5 to 1.0 mmol/L for 12 hours significantly increased mRNA of GRP78 and CHOP,and decreased that of Bcl-2 compared to control (P ＜0.001),with the maximum concentration being 0.75 mmol/L.Palmitate 0.5 mmol/L loading for 3 hours,8 hours,and 12 hours significantly increased mRNA of GRP78 and CHOP,and decreased that of Bcl-2 compared to 0 hour (P ＜0.001),with the maximum effect at 3 hours.Confocal microscopy demonstrated that GRP78 expression was significantly increased when exposed to 0.5 mmol/L of palmitate for 8 hours compared to control.Conclusion Palmitate could induce podocyte apoptosis via ER stress,suggesting podocyte apoptosis and consequent proteinuria caused by lipotoxic free fatty acid could be ameliorated by relief of ER stress.
- [1]Mao XD,Lu YB,Xu KF,etc.Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes.[J].2008,28(6).
- [2]T W, Meyer,P H, Bennett,R G, Nelson.Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria.[J].1999,42(11).
- [3]Klotz LO,Martindale JL,Holbrook NJ,etc.Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state.[J].2001,21(4).
- [4]Kitao Y,Nangaku M,Onogi H,etc.Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation.[J].2005,68(6).
- [5]Tabas I,Ron D.Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress.[J].2011,13(3).
- [6]Sieber J,Lindenmeyer MT,Kampe K,etc.Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids.[J].2010,299(4 Pt.2).
- [7]Mathieson PW.Update on the podocyte.[J].2009,18(3).
- [8]Dimopoulos N,Watson M,Sakamoto K,etc.Differential effects of palmitate and palmitoleate on insulin action and glucose utilization in rat L6 skeletal muscle cells[J].2006,399(3).
- [9]Ziyadeh FN,Wolf G,Chen S.From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy.[J].2005,54(6).
- [10]Jumping Eagle S,Pagtalunan ME,Nelson RG,etc.Podocyte loss and progressive glomerular injury in type II diabetes.[J].1997,99(2).
- [11]Peter Mundel,Jochen Reiser,Aimée Zúñiga Mejı́a Borja,etc.Rearrangements of the Cytoskeleton and Cell Contacts Induce Process Formation during Differentiation of Conditionally Immortalized Mouse Podocyte Cell Lines[J].1997,236(1).
- [12]Mooradian AD.Dyslipidemia in type 2 diabetes mellitus.[J].2009,5(3).
- [13]Dalla Vestra M,Roiter AM,Masiero A,etc.Is podocyte injury relevant in diabetic nephropathy?: studies in patients with type 2 diabetes.[J].2003,52(4).
- [14]Weinberg JM.Lipotoxicity.[J].2006,70(9).
- [15]Susztak K,Raff AC,Schiffer M,etc.Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy.[J].2006,55(1).
- [16]Del Vecchio L,Pozzoni P,Locatelli F.Renal replacement therapy in patients with diabetes and end-stage renal disease.[J].2004,15(Suppl.1).
- [17]Reiko Inagi.Endoplasmic Reticulum Stress in the Kidney as a Novel Mediator of Kidney Injury[J].2009,112(1).
- [18]Ni, Min,Zhang, Yi,Lee, Amy S. ..Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting[J].2011,434(2).
- [19]Pagliassotti MJ,Topczewski F,Wei Y,etc.Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.[J].2006,291(2).
- [20]Cybulsky AV.Endoplasmic reticulum stressin proteinuric kidney disease.[J].2010,77(3).
- [21]Sibler RA,von Eckardstein A.Possible contributions of lipoproteins and cholesterol to the pathogenesis of diabetes mellitus type 2.[J].2011,22(1).
- [22]E, SHAFRIR.Partition of unesterified fatty acids in normal and nephrotic syndrome serum and its effect on serum electrophoretic pattern.[J].1958,37.