Deletion of MK2 signalling in vivo inhibits small Hsp phosphorylation but not diabetic nephropathy

Park, Joon-Keun; Ronkina, Natalia; Höft, Andreas; Prohl, Corinna; Menne, Jan; Gaestel, Matthias; Haller, Hermann; Meier, Matthias

doi:10.1093/ndt/gfm917

Cited by 12 publications

(18 citation statements)

References 37 publications

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“…Both the pattern of staining and costaining with the podocyte marker synaptopodin suggest a localization to the glomerular podocytes. Previous studies have reported an increase in the phosphorylated form of HSP25 in the diabetic glomeruli (6,21,23), but this is the first study that identifies the specific glomerular cell type involved. Furthermore, our in vitro data show that podocyte exposure to stretch, mimicking glomerular capillary hypertension, induces a rapid and significant 4.4-fold increase in the levels of phosphorylated HSP27.…”

Section: Discussionmentioning

confidence: 77%

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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: 77%

“…In contrast, Park et al (23) have recently reported that albuminuria is not ameliorated in diabetic mice knockout for MK2. However, in this study HSP27 phosphorylation was only partially prevented, and it is known that not only MK2, but also MK3 can phosphorylate HSP27 on the same serine residues (4).…”

Section: Discussionmentioning

confidence: 84%

Heat shock protein expression in diabetic nephropathy

Barutta¹,

Pinach²,

Giunti³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…57 Indeed, high glucose promotes HSPB1 phosphorylation in renal cells in an MK(MAPKAP)-2-dependent manner. 58 The phosphorylation state of HSPB1 can influence its function. Thus, it modulates the size of HSPB1 oligomers and facilitates the nuclear migration of the protein.…”

Section: Discussionmentioning

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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“…[44][45][46] 44 HSP25 is phosphorylated by upstream p38 mitogenactivated protein kinase (p38MAPK). [47][48][49] A study showed synchronized activation of the glomerular p38MAPK-HSP25 pathway, acutely after the induction of diabetes with streptozotocin (Stz-DM) in rats, together with conservation of the podocyte actin cytoskeleton and normo-albuminuria.…”

Section: Hsp27 In Diabetic Nephropathymentioning

confidence: 99%

“…54 Animal models of nephrotic syndrome and DN showed enhanced HSP27 phosphorylation compared to control animals. 44,46,55 Abnormal HSP27 phosphorylation is also observed in renal cancers, as well as in other kidney diseases. 56 Furthermore, over-expression of HSP27 has been contributed to tumor progression in a variety of cancers including Renal Cell Carcinoma (RCC).…”

Section: Abnormal Hsp27 Phosphorylation In Kidney Diseasementioning

confidence: 99%