Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease

Liu, Guanghui; Sun, Yingying; Li, Zhenhua; Song, Tao; Wang, Haibin; Zhang, Yun; Ge, Zhiming

doi:10.1016/j.bbrc.2008.04.031

Cited by 154 publications

(124 citation statements)

References 38 publications

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“…1,11 Of note, these studies frequently used a TUNEL assay to detect apoptosis. 1,11,20,21 However, the TUNEL assay is not specific for apoptosis and additionally detects other cell-death forms. 22,23 Importantly, both interventions, CIX and M-920, reduced glomerular cell death and in situ caspase-3/7 activity in this study, but the CIX inhibitor nevertheless failed to protect from dNP.…”

mentioning

confidence: 99%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

103

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Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1b), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucosestressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.

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mentioning

confidence: 99%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

103

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“…8 Previous evidences have demonstrated that ER stress may contribute to the development of DN. [9][10][11] Autophagy, an essential process for basal homeostasis, acts as a mechanism to keep homeostatic balance by degrading damaged cellular organelles and proteins. 12 Defective autophagy accelerates the irreparable progression of DN in mice.…”

mentioning

confidence: 99%

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Wang

Chen

et al. 2016

Laboratory Investigation

104

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Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded and/or unfolded proteins in ER membranes, is involved in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the role of ER stress inhibitors ursodeoxycholic acid (UDCA) and 4-phenylbutyrate (4-PBA) in the treatment of DN in db/db mice. Findings have revealed that diabetic db/db mice were more hyperglycemic than their non-diabetic controls, and exhibited a marked increase in body weight, water intake, urine volume, fasting plasma glucose, systolic blood pressure, glucose and insulin tolerance. UDCA (40 mg/kg/day) or 4-PBA (100 mg/kg/day) treatment for 12 weeks resulted in an improvement in these biochemical and physical parameters. Moreover, UDCA or 4-PBA intervention markedly decreased urinary albuminuria and attenuated mesangial expansion in diabetic db/db mice, compared with db/db mice treated with vehicle. These beneficial effects of UDCA or 4-PBA on DN were associated with the inhibition of ER stress, as evidenced by the decreased expression of BiP, phospho-IRE1α, phospho-eIF2α, CHOP, ATF-6 and spliced X-box binding protein-1 in vitro and in vivo. UDCA or 4-PBA prevented hyperglycemia-induced or high glucose (HG)-induced apoptosis in podocytes in vivo and in vitro via the inhibition of caspase-3 and caspase-12 activation. Autophagy deficiency was also seen in glomeruli in diabetic mice and HG-incubated podocytes, exhibiting decreased expression of LC3B and Beclin-1, which could be restored by UDCA or 4-PBA treatment. Taken together, our results have revealed an important role of ER stress in the development of DN, and UDCA or 4-PBA treatment may be a potential novel therapeutic approach for the treatment of DN.

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“…Compared with other reports of CHOP in kidneys during diabetes (Brezniceanu et al 2010;Liu et al 2008), this is the first report of increased CHOP Fig. 6 Overexpression of CHOP in proximal tubule cells.…”

Section: Discussionmentioning

confidence: 50%

“…Early in diabetes, tubules undergo hypertrophy and expansion of the basement membrane and eventually atrophy and dilatation by the time DN is established (Hryciw et al 2004;Magri and Fava 2009;Thomas et al 2005). The presence of endoplasmic reticulum (ER) stress-response and ER stress-induced apoptotic markers has been shown in kidneys during diabetes (Brezniceanu et al 2010;Zhuang and Forbes 2014;Lindenmeyer et al 2008;Liu et al 2008;Wu et al 2010a, b). However, since the majority of the studies were conducted by analysis of markers in whole kidney homogenates, this stress response has not been clearly defined in different renal structures or tubule segments at different stages of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice

Barati

Powell

Kechavarzi

et al. 2016

Cell Stress and Chaperones

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Regulation of the endoplasmic reticulum (ER) stress-response pathway during the course of diabetes specifically in renal tubules is unclear. Since tubule cell dysfunction is critical to progression of diabetic nephropathy, this study analyzed markers of ER stress response and ER chaperones at different stages of diabetes and in different renal tubule subtypes of OVE26 type-1 diabetic mice. ER stress-responseinduced chaperones GRP78, GRP94, and protein disulfide isomerase (PDI) were increased in isolated cortical tubules of older diabetic mice, while PDI was decreased in tubules of young diabetic mice. Immunofluorescence staining of kidneys from older mice showed GRP78 and PDI upregulation in all cortical tubule segments, with substantial induction of PDI in distal tubules. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) phosphorylation was increased in cortical tubules of young diabetic mice, with no differences between older diabetic and control mice. Expression of ER stress-induced PERK inhibitor p58 IPK was decreased and then increased in all tubule subtypes of young and older mice, respectively. Knockdown of PERK by small interfering RNA (siRNA) increased fibronectin secretion in cultured proximal tubule cells. Tubules of older diabetic mice had significantly more apoptotic cells, and ER stress-induced proapoptotic transcription factor C/EBP homologous protein (CHOP) was increased in proximal and distal tubules of diabetic mice and diabetic humans. CHOP induction in OVE26 mice was not altered by severity of proteinuria. Overexpression of CHOP in cultured proximal tubule cells increased expression of fibronectin. These findings demonstrate differential ER stress-response signaling in tubule subtypes of diabetic mice and implicate a role for PERK and CHOP in tubule cell matrix protein production.

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Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease

Cited by 154 publications

References 38 publications

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice

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