BASP1 Promotes Apoptosis in Diabetic Nephropathy

Sanchez-Niño, María Dolores; Sanz, Ana B.; Lorz, Corina; Gnirke, Andrea; Rastaldi, Maria Pia; Nair, Viji; Egido, Jesús; Ruíz-Ortega, Marta; Kretzler, Matthias; Ortíz, Alberto

doi:10.1681/asn.2009020227

Cited by 81 publications

(80 citation statements)

References 54 publications

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“…Many disease conditions in the kidney are associated with excessive apoptosis, such as diabetic nephropathy, 34,35 glomerular tubular disconnection in diseases with profound proteinuria, 36 polycystic kidney disease, 37 and AKI. 38 Expression of Bax is increased in many of these conditions, leading to the suggestion that the Bax inhibitor Bcl-xL would be a potential therapeutic target in renal diseases associated with apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

Burlaka

Liu

Rebetz

et al. 2013

Journal of the American Society of Nephrology

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Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-kB pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-kB antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.

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Section: Discussionmentioning

confidence: 99%

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

Burlaka

Liu

Rebetz

et al. 2013

Journal of the American Society of Nephrology

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“…62 After 48 h, the transfected cells were harvested for Western blot or PCR analysis. siRNA were synthesized by Santa Cruz Biotechnology.…”

Section: Sirna Transfectionmentioning

confidence: 99%

The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

Moreno

Izquierdo²,

Sanchez-Niño³

et al. 2011

Journal of the American Society of Nephrology

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336

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Proinflammatory cytokines contribute to renal injury, but the downstream effectors within kidney cells are not well understood. One candidate effector is Klotho, a protein expressed by renal cells that has antiaging properties; Klotho-deficient mice have an accelerated aging-like phenotype, including vascular injury and renal injury. Whether proinflammatory cytokines, such as TNF and TNF-like weak inducer of apoptosis (TWEAK), modulate Klotho is unknown. In mice, exogenous administration of TWEAK decreased expression of Klotho in the kidney. In the setting of acute kidney injury induced by folic acid, the blockade or absence of TWEAK abrogated the injury-related decrease in renal and plasma Klotho levels. TWEAK, TNF␣, and siRNA-mediated knockdown of IB␣ all activated NFB and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NFB with parthenolide prevented TWEAK-or TNF␣-induced downregulation of Klotho. Inhibition of histone deacetylase reversed TWEAKinduced downregulation of Klotho, and chromatin immunoprecipitation showed that TWEAK promotes RelA binding to the Klotho promoter, inducing its deacetylation. In conclusion, inflammatory cytokines, such as TWEAK and TNF␣, downregulate Klotho expression through an NFB-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD.

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“…33 The primary antibodies were goat polyclonal anti-HSPB1 (1:60, Santa Cruz Biotechnology, CA, USA) and FITC-mouse anti-synaptopodin (1:10, Progen, Heidelberg, Germany). Secondary HRP-and phycoerythrin-conjugated antibodies were used for HSPB1.…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II

Sanchez-Niño

Sanz

Sánchez-López

et al. 2012

Laboratory Investigation

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Apoptosis is a driving force of diabetic end-organ damage, including diabetic nephropathy (DN). However, the mechanisms that modulate diabetes-induced cell death are not fully understood. Heat shock protein 27 (HSP27/HSPB1) is a cell stress protein that regulates apoptosis in extrarenal cells and is expressed by podocytes exposed to toxins causing nephrotic syndrome. We investigated the regulation of HSPB1 expression and its function in podocytes exposed to factors contributing to DN, such as high glucose and angiotensin (Ang) II. HSPB1 expression was assessed in renal biopsies from patients with DN, minimal change disease or focal segmental glomerulosclerosis (FSGS), in a rat model of diabetes induced by streptozotocin (STZ) and in Ang II-infused rats. The regulation of HSPB1 was studied in cultured human podocytes and the function of HSPB1 expressed in response to pathophysiologically relevant stimuli was explored by short interfering RNA knockdown. Total kidney HSPB1 mRNA and protein expression was increased in rats with STZ-induced diabetes and in rats infused with Ang II. Upregulation of HSPB1 protein was confirmed in isolated diabetic glomeruli. Immunohistochemistry showed increased glomerular expression of HSPB1 in both models and localized glomerular HSPB1 to podocytes. HSPB1 protein was increased in glomerular podocytes from patients with DN or FSGS. In cultured human podocytes HSPB1 mRNA and protein expression was upregulated by high glucose concentrations and Ang II. High glucose, but not Ang II, promoted podocyte apoptosis. HSPB1 short interfering RNA (siRNA) targeting increased apoptosis in a high-glucose milieu and sensitized to Ang II or TGFb1-induced apoptosis by promoting caspase activation. In conclusion, both high glucose and Ang II contribute to HSPB1 upregulation. HSPB1 upregulation allows podocytes to better withstand an adverse high-glucose or Ang II-rich environment, such as can be found in DN.

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BASP1 Promotes Apoptosis in Diabetic Nephropathy

Cited by 81 publications

References 54 publications

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II

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