Altered expression of glomerular heat shock protein 27 in experimental nephrotic syndrome.

Smoyer, William E.; Gupta, Avneesh; Mündel, Peter; Ballew, Jeffrey D.; Welsh, Michael J.

doi:10.1172/jci118723

Cited by 69 publications

(70 citation statements)

References 43 publications

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“…The observation that in experimental nephrotic syndrome foot process effacement and proteinuria are paralleled by enhanced HSP27 phosphorylation in the foot processes (32) and that in vitro TNF-␣ enhances transendothelial permeability via a P38-phospho-HSP27 mechanism (16) has led to the hypothesis that HSP27 phosphorylation plays a role Fig. 6.…”

Section: Discussionmentioning

confidence: 99%

“…Both hyperglycemia and glomerular capillary hypertension impose cellular stresses on renal target cells and they are thus potential inducers of a stress response that may counterbalance the deleterious effects of these insults. In addition, enhanced expression/phosphorylation of HSP27, an actin-specific molecular chaperone, has been reported in podocytes in experimental nephrotic syndrome (32), suggesting a role for HSP27 in the pathophysiological changes of the podocyte cytoskeleton during the development of proteinuria. Liu et al (19) have demonstrated that HSP47, a procollagen-specific molecular chaperon, is overexpressed within the glomeruli in both early and advanced diabetic nephropathy, but little is known about the effect of diabetes and diabetes-related insults on other members of this family of proteins.…”

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confidence: 99%

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Heat shock protein expression in diabetic nephropathy

Barutta¹,

Pinach²,

Giunti³

et al. 2008

American Journal of Physiology-Renal Physiology

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Heat shock protein (HSP) HSP27, HSP60, HSP70, and HSP90 are induced by cellular stresses and play a key role in cytoprotection. Both hyperglycemia and glomerular hypertension are crucial determinants in the pathogenesis of diabetic nephropathy and impose cellular stresses on renal target cells. We studied both the expression and the phosphorylation state of HSP27, HSP60, HSP70, and HSP90 in vivo in rats made diabetic with streptozotocin and in vitro in mesangial cells and podocytes exposed to either high glucose or mechanical stretch. Diabetic and control animals were studied 4, 12, and 24 wk after the onset of diabetes. Immunohistochemical analysis revealed an overexpression of HSP25, HSP60, and HSP72 in the diabetic outer medulla, whereas no differences were seen in the glomeruli. Similarly, exposure neither to high glucose nor to stretch altered HSP expression in mesangial cells and podocytes. By contrast, the phosphorylated form of HSP27 was enhanced in the glomerular podocytes of diabetic animals, and in vitro exposure of podocytes to stretch induced HSP27 phosphorylation via a P38-dependent mechanism. In conclusion, diabetes and diabetesrelated insults differentially modulate HSP27, HSP60, and HSP70 expression/phosphorylation in the glomeruli and in the medulla, and this may affect the ability of renal cells to mount an effective cytoprotective response. mesangial cells; glomerular epithelial cells; mechanical stretch DIABETIC NEPHROPATHY (DN), the leading cause of end-stage renal failure in the Western world, is characterized by increased albumin excretion rate (AER) and progressive decline in renal function (9,20). Both hyperglycemia and glomerular capillary hypertension are considered major determinants in the onset and the progression of the complication (5), and in vitro studies on renal cells exposed to high glucose and/or mechanical stretch have partially clarified the underlying cellular mechanisms for this disorder (13).Heat shock proteins (HSP) are ubiquitous, highly evolutionary conserved intracellular proteins categorized according to their molecular weight (10). Thermal, oxidative, hemodynamic, osmotic, and hypoxic stresses (17) induce HSP60, HSP27 (human)/HSP25 (rodents), and HSP70 (human)/HSP72 (rodents), and HSP90 expression, and this stress response results in cytoprotection (18). Specifically, HSP prevent nonspecific protein assembly, assist in denatured protein refolding, and interfere with proapoptotic pathways. Both hyperglycemia and glomerular capillary hypertension impose cellular stresses on renal target cells and they are thus potential inducers of a stress response that may counterbalance the deleterious effects of these insults. In addition, enhanced expression/phosphorylation of HSP27, an actin-specific molecular chaperone, has been reported in podocytes in experimental nephrotic syndrome (32), suggesting a role for HSP27 in the pathophysiological changes of the podocyte cytoskeleton during the development of proteinuria. Liu et al. (19) have demonstrated that HSP47, a procolla...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Heat shock protein expression in diabetic nephropathy

Barutta¹,

Pinach²,

Giunti³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…[25][26][27][28][29][30] HSPB1 may be of particular interest in podocyte injury because its expression is induced by the podocyte toxin puromycin aminonucleoside (PAN). 31 Protective cellular responses in podocytes are poorly understood. HSPB1 regulates actin microfilament dynamics in podocyte foot processes.…”

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confidence: 99%

“…HSPB1 regulates actin microfilament dynamics in podocyte foot processes. 31 In addition, enhanced podocyte HSPB1 expression/phosphorylation has been reported in experimental nephrotic syndrome induced by the podocyte toxin PAN 31 suggesting a role for HSPB1 in the pathophysiological changes of the podocyte cytoskeleton during the development of proteinuria. However, there is an incomplete understanding of the relationship between podocyte HSPB1 and stressors relevant to DN, such as high glucose and Ang II.…”

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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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“…Enhanced HSP27 expression/phosphorylation in podocytes was reported in experimental nephrotic syndrome, suggesting that HSP27 may regulate polymerization of GEC foot process actin, maintaining normal foot process structure along with its implication in the pathophysiologic changes in these processes during development of the nephrotic syndrome. 70 …”

Section: Hsp27 In Nephrotic Syndromementioning

confidence: 99%