Mechanical Deformation Induced Apoptosis in Human Proximal Renal Tubular Epithelial Cells is Caspase Dependent

Power, Richard E.; Doyle, Belinda T.; Higgins, Debra F.; Brady, Hugh R.; Fitzpatrick, John M.; Watson, R. William G.

doi:10.1097/01.ju.0000091106.61065.e3

Cited by 42 publications

(40 citation statements)

References 14 publications

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“…Accordingly, previous studies have shown that neither oxidative and nor osmotic stress induces HSP27 and HSP70 expression in mesangial cells (8,21). Lack of response to these insults appears to be specific to glomerular cells as stretch has been shown to induce HSP70 overexpression in other cell types such as tubular epithelial cells (26) and vascular smooth muscle cells (36). Furthermore, our observation that both HSP27 and HSP70 are strongly induced by exposure to thermal stress indicates that the inability to mount an effective stress response is limited to diabetes-related insults.…”

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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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%

Heat shock protein expression in diabetic nephropathy

Barutta¹,

Pinach²,

Giunti³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…Intraluminal pressure can also be dramatically elevated in kidney disease states [11]. Indeed, obstructive uropathy is associated with a major increase in intratubular pressure, in excess of 60 mm Hg, leading to tubular circumferential stretch [16][17][18][19][20]. Stretching as well as compression of renal epithelial cells also occur in polycystic kidney disease (PKD) patients [11].…”

Section: Introductionmentioning

confidence: 99%

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

et al. 2013

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Mechanical forces associated with fluid flow and/or circumferential stretch are sensed by renal epithelial cells and contribute to both adaptive or disease states. Non-selective stretch-activated ion channels (SACs), characterized by a lack of inactivation and a remarkably slow deactivation, are active at the basolateral side of renal proximal convoluted tubules. Knockdown of Piezo1 strongly reduces SAC activity in proximal convoluted tubule epithelial cells. Similarly, overexpression of Polycystin-2 (PC2) or, to a greater extent its pathogenic mutant PC2-740X, impairs native SACs. Moreover, PC2 inhibits exogenous Piezo1 SAC activity. PC2 coimmunoprecipitates with Piezo1 and deletion of its N-terminal domain prevents both this interaction and inhibition of SAC activity. These findings indicate that renal SACs depend on Piezo1, but are critically conditioned by PC2.

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“…Interestingly, the pathways of programmed cell death can be activated by mechanical stretch, alone. Caspase 3-mediated apoptosis is induced by applying gentle stretch to the substratum on which monolayers of human kidney cells are cultured (20). Similarly, mechanical strain was shown to activate BAD dephosphorylation in cultured proximal tubular cells (15).…”

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confidence: 99%

PAX2 is reactivated in urinary tract obstruction and partially protects collecting duct cells from programmed cell death

Cohen¹,

Loutochin²,

Amin³

et al. 2007

American Journal of Physiology-Renal Physiology

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Obstruction of the urinary tract activates apoptotic pathways in collecting duct cells and leads to loss of renal parenchyma before surgical intervention. It has been suggested that developmental pathways may be reactivated to offset acute organ damage. One such molecule, PAX2, is expressed throughout the fetal collecting duct and was recently shown to suppress apoptosis during kidney development. We hypothesized that acute unilateral urinary tract obstruction (UUO) reactivates PAX2 expression in the mature kidney and partially suppresses apoptosis. If so, animals with PAX2 mutations should have increased susceptibility to parenchymal damage. Wild-type and heterozygous Pax2 mutant (C3H/ Pax2 1Neu) mice underwent unilateral ureteric ligation or sham operation at 6 wk of age; kidneys were examined after 5, 10, and 15 days. Whereas PAX2 protein levels fell to low levels in the first weeks of life, it was sharply reactivated by day 10 in collecting duct cells of wild-type but not in Pax2 1Neu mutant mice with UUO. Wild-type mice with UUO had marked TUNEL and cleaved spectrin staining in tubular cells and reduced kidney weight after 10–15 days. Mutant mice had exaggerated increases in markers of apoptosis and exaggerated loss of renal parenchymal loss in the obstructed kidney. These observations suggest that PAX2 is rapidly reactivated in UUO and that mice with genetically limited PAX2 expression have heightened susceptibility to apoptosis.

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Mechanical Deformation Induced Apoptosis in Human Proximal Renal Tubular Epithelial Cells is Caspase Dependent

Abstract: Altering HSP-70 expression and manipulating the caspase cell death proteases represent a novel pathway to protect against renal tubular cell apoptosis and the potential for progression to renal failure in UO.

Cited by 42 publications

References 14 publications

Heat shock protein expression in diabetic nephropathy

Heat shock protein expression in diabetic nephropathy

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

PAX2 is reactivated in urinary tract obstruction and partially protects collecting duct cells from programmed cell death

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