Glucose loading induces DNA fragmentation in rat proximal tubular cells

Ishii, Naohito; Ogawa, Zensuke; Suzuki, Katsuo; Numakami, Kiyohiko; Saruta, Takao; Itoh, Hajime

doi:10.1016/s0026-0495(96)90114-6

Cited by 41 publications

(25 citation statements)

References 29 publications

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“…The readily noticeable injury seems to be apoptosis of tubular cells (Figures 1 and 2), which evidently is also seen in the rat model of acute ischemia-reperfusion injury or after intravenous loading of high concentration of glucose (55 mM). 24,25 That moderately high blood glucose levels or in vitro exposure of 15 to 35 mM D-glucose also induced apoptosis in tubular cells suggests that mechanisms other than osmotic injury are involved. In this regard, many studies indicate that a number of genes modulating various cellular events and pathways are affected in cells undergoing apoptosis in a wide variety of model systems.…”

Section: Discussionmentioning

confidence: 99%

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Sun

Xie²,

Wada

et al. 2008

Journal of the American Society of Nephrology

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The role of tubular injury in diabetic nephropathy is relatively unknown, despite that apoptosis of tubular epithelial cells is commonly observed in human renal biopsies. The GTPase Ras-proximate-1 (Rap1b) is upregulated in the hyperglycemic state and is known to increase B-Raf, an antiapoptotic effector protein.In this study, the effects of high glucose on renal tubular apoptosis and the potential ability for Rap1b to ameliorate these effects were investigated. In the kidneys of diabetic mice, apoptotic tubular cells and dysmorphic mitochondria were observed, Bcl-2 expression was decreased, and Bax expression was increased. Total Rap1b expression was slightly increased, but its associated GTPase activity was significantly decreased. In vitro, high extracellular glucose led to decreased Bcl-2 expression, reduced Rap1b GTPase activity, and increased levels of both Bax and GTPase activating protein in a proximal tubular cell line (HK-2). These changes were accompanied by increased DNA fragmentation, decreased high molecular weight mitochondrial DNA, altered mitochondrial morphology and function, disrupted Bcl-2-Bax and Bcl-2-Rap1b interactions, and reduced cell survival. Overexpression of Rap1b partially prevents these abnormalities. Furthermore, the BH4 domain of Bcl-2 was found to be required for successful protein-protein interaction between Bcl-2 and Rap1b. In summary, these data suggest that Rap1b ameliorates glucose-induced mitochondrial dysfunction in renal tubular cells.

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Section: Discussionmentioning

confidence: 99%

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Sun

Xie²,

Wada

et al. 2008

Journal of the American Society of Nephrology

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“…In vitro, murine tubular cells cultured in high-glucose medium for 1–4 days exhibit downregulation of the bcl-2 gene and bclx mRNA, with a twofold increase in the apoptosis index [16]. DNA fragmentation was also seen after intravenous infusion of 10% glucose in extracts from isolated tubular cells of male Wistar rats [17]. …”

Section: Discussionmentioning

confidence: 99%

Glomerular Cell Replication and Cell Loss through Apoptosis in Experimental Diabetes mellitus

Pesce

Menini

Pricci

et al. 2002

Nephron

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Aim: To evaluate changes in the glomerular cell balance between replication and apoptosis in experimental diabetes mellitus (DM) in relation to morphometric data. Methods: Adult Sprague-Dowley rats with streptozotocin-induced DM and controls of the same age and strain were sacrificed 4 and 8 weeks and 6 months after disease onset. Cell replication was demonstrated with MIB-5, and apoptosis with the terminal uridine nick end labeling technique. Glomerular size and glomerular cell population were estimated morphologically. Results: Diabetic and control rats showed irrelevant MIB-5 positivity at all time points. Glomerular apoptosis was minimal in rats with 4 and 8 weeks of DM and in controls. Rats with 6 months of DM showed significantly higher glomerular apoptosis values than controls (2.49 ± 0.25 vs. 0.65 ± 0.16%; p < 0.001). The mean cell count per glomerular profile was significantly lower in these diabetic rats (64.02 ± 1.93 vs. 78.27 ± 0.99; p < 0.001), a change that correlated with that in apoptosis. The glomerular cell density was further decreased in diabetic rats because of the diabetic increase in mean glomerular volume (1.598 vs. 0.927 10⁶ µm). Conclusions: Apoptosis is associated with loss of glomerular cells in rats with long-term, streptozotocin-induced DM and – to a considerably lower degree – in controls of the same age and strain. These changes could be relevant to glomerulosclerosis associated with long-term, streptozotocin-induced DM.

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“…The possibility that hyperglycemia directly mediates apoptotic cell death is suggested by in vitro studies wherein exposure to high levels of glucose causes apoptosis in preimplantation embryos [8], cultured endothelial cells [9, 10], pancreatic beta cells [11], and renal proximal tubules [12]. Although glucose may at least partly mediate the apoptotic response, a deficiency of insulin could also play a role.…”

Section: Introductionmentioning

confidence: 99%

Tubular and Interstitial Cell Apoptosis in the Streptozotocin-Diabetic Rat Kidney

Kumar

Zimpelmann²,

Robertson³

et al. 2004

Nephron Exp Nephrol

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Background/Aims: Angiotensin II (Ang II) mediates progressive nephron loss in diabetes and stimulates apoptotic cell death in several tissues. We studied the extent of apoptosis in streptozotocin (STZ) induced diabetic nephropathy in the rat and the effects of insulin and type 1 (AT₁) or type 2 (AT₂) Ang II receptor blockade with losartan or PD123319, respectively. Methods: Three groups of rats were studied after 2 and 12 weeks: (1) controls ; (2) STZ-diabetic rats (STZ rats), and (3) STZ-diabetic rats with insulin implants. Additional rats were treated with losartan (25 mg/kg/day) and/or PD123319 (10 mg/kg/day) for 2 weeks. Kidneys were examined for apoptosis, using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, DNA laddering, and electron microscopy. Immunoblotting determined expression of the proapoptotic protein Bax and of the antiapoptotic protein Bcl-2 in proximal tubules. Results: Diabetes caused a significant increase in apoptosis, involving tubular and interstitial cells of cortex and medulla, but not glomerular cells (2 weeks: controls 264 ± 94 vs. STZ rats 1,501 ± 471 apoptotic nuclei/kidney section; p < 0.02; n = 6–8), an effect reversed by insulin. In STZ rats, ultrastructural examination revealed chromatin condensation and nuclear fragmentation in tubular and interstitial cells. At 2 and 12 weeks, a significant decrease in the expression of the antiapoptotic protein Bcl-2 occurred in STZ rat proximal tubules, with restoration by insulin. In STZ rats, treatment for 2 weeks with losartan or PD123319 inhibited apoptosis in the kidneys, with no additive effect of the combination therapy. Conclusions: Apoptosis occurs in diabetic nephropathy, involving tubular and interstitial cells, an effect reversed by insulin therapy. Furthermore, the effects of AT₁ or AT₂ receptor blockade suggest that Ang II is involved in mediating apoptosis in the diabetic kidney.

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Glucose loading induces DNA fragmentation in rat proximal tubular cells

Cited by 41 publications

References 29 publications

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Glomerular Cell Replication and Cell Loss through Apoptosis in Experimental Diabetes mellitus

Tubular and Interstitial Cell Apoptosis in the Streptozotocin-Diabetic Rat Kidney

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