Glucose and diabetes: Effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton

Dai, Tiane; Natarajan, Rama; Nast, Cynthia C.; LaPage, Janine; Chuang, Peter Y.; Sim, John J.; Tong, Lili; Chamberlin, M; Wang, S; Adler, Sharon G.

doi:10.1038/sj.ki.5000033

Cited by 43 publications

(48 citation statements)

References 46 publications

(63 reference statements)

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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: 82%

“…Stretch-induced HSP27 phosphorylation was mediated by a P38-dependent mechanism as the application of stretch induced a significant twofold increase in activated P38 levels, with P38 inhibition completely abolishing HSP27 phosphorylation. Similarly, high glucose-induced HSP27 phosphorylation is P38 dependent in podocytes (6), and a P38-MAPKactivated protein kinase 2/3 (MK2/3) pathway has been implicated in HSP27 phosphorylation in various cell types (4).…”

Section: Discussionmentioning

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: 82%

Section: Discussionmentioning

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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“…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%

“…However, when Stz-DM becomes chronic, activation of this pathway declines, cleavage of F-actin produces G-actin monomers, and podocyte effacement (retraction) and albuminuria occur. 44 With these associations, Ma et al hypothesized that early activation of that pathway might be a functional adaptation that maintained podocyte structure and function and prevented glucose stressor induced albuminuria. 50 Furthermore, HSP27 up-regulation in response to injurious high-glucose or Angiotensin II-rich environment, as in diabetic nephropathy (DN), forbids podocytes apoptosis and improves their tolerance to those adverse stressors 51 .…”

Section: Hsp27 In Diabetic Nephropathymentioning

confidence: 99%

“…[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%

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Heat Shock Protein 27(HSP27) in Kidney Disease: Potentials for Diagnosis and Therapy

Mahgoub

2017

Journal of Advanced Pharmacy Research

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Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

219

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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Glucose and diabetes: Effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton

Cited by 43 publications

References 46 publications

Heat shock protein expression in diabetic nephropathy

Heat shock protein expression in diabetic nephropathy

Heat Shock Protein 27(HSP27) in Kidney Disease: Potentials for Diagnosis and Therapy

Pathophysiology of the Diabetic Kidney

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