Recovery of cellular functions following oxidant injury

Nowak, Graz ̇yna; Aleo, Michael D.; Morgan, Jan A.; Schnellmann, Rick G.

doi:10.1152/ajprenal.1998.274.3.f509

Cited by 30 publications

(38 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously demonstrated that oxidant exposure (i.e. TBHP) decreases mitochondrial function and that mitochondrial function returns over a period of days to control levels (27,28). In this paper, we have shown that the loss of mitochondrial function is associated mitochondrial damage and autophagy.…”

Section: Discussionmentioning

confidence: 63%

“…AMP kinase is activated in response to cell stressors causing perturbations in cAMP/ATP ratios (44), can participate in the activation of the p38MAPK-signaling cascade (4,45), and has been implicated in regulating the expression of PGC-1␣ in muscle in response to a variety of stimuli (36, 46 -49). Because rapid decreases in cellular ATP are observed in TBHP-treated RPTCs (28) and AMP kinase is known to be activated under conditions of renal ischemia (50), it is possible that AMP kinase is activated following oxidant treatment in our model and will be the subject of future experiments.…”

Section: Discussionmentioning

confidence: 99%

“…These changes in renal proximal tubular cell (RPTC) energetics also are observed in cellular models subjected to diverse stresses (22-26). For example, sublethally injured RPTCs exhibit mitochondrial dysfunction, such as decreases in oxygen consumption and ATP levels, following exposure to the model oxidant tert-butylhydroperoxide that spontaneously recovers over the course of six days (27,28). The recovery of mitochondrial function is temporally related to RPTC de-differentiation, migration, and proliferation, and complete recovery of mitochondrial function is associated with RPTC redifferentiation (28,29).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Signaling of Mitochondrial Biogenesis following Oxidant Injury

Rasbach¹,

Schnellmann

2007

Journal of Biological Chemistry

Self Cite

142

View full text Add to dashboard Cite

Mitochondrial dysfunction is a common consequence of ischemia-reperfusion and drug injuries. For example, sublethal injury of renal proximal tubular cells (RPTCs) with the model oxidant tert-butylhydroperoxide (TBHP) causes mitochondrial injury that recovers over the course of six days. Although regeneration of mitochondrial function is integral to cell repair and function, the signaling pathway of mitochondrial biogenesis following oxidant injury has not been examined. A 10-fold overexpression of the mitochondrial biogenesis regulator PPAR-␥ cofactor-1␣ (PGC-1␣) in control RPTCs resulted in a 52% increase in mitochondrial number, a 27% increase in respiratory capacity, and a 30% increase in mitochondrial protein markers, demonstrating that PGC-1␣ mediates mitochondrial biogenesis in RPTCs. RPTCs sublethally injured with TBHP exhibited a 50% decrease in mitochondrial function and increased mitochondrial autophagy. Compared with the controls, PGC-1␣ levels increased 12-fold on days 1, 2, and 3 post-injury and returned to base line on day 4 as mitochondrial function returned. Inhibition p38 MAPK blocked the up-regulation of PGC-1␣ following oxidant injury, whereas inhibition of calcium-calmodulindependent protein kinase, calcineurin A, nitric-oxide synthase, and phosphoinositol 3-kinase had no effect. The epidermal growth factor receptor (EGFR) was activated following TBHP exposure, and the EGFR inhibitor AG1478 blocked the up-regulation of PGC-1␣. Additional inhibitor studies revealed that the sequential activation of Src, p38 MAPK, EGFR, and p38 MAPK regulate the expression of PGC-1␣ following oxidant injury. In contrast, although Akt was activated following oxidant injury, it did not play a role in PGC-1␣ expression. We suggest that mitochondrial biogenesis following oxidant injury is mediated by p38 and EGFR activation of PGC-1␣.3 is a 92-kDa protein that was first identified as a regulator of adaptive thermogenesis in brown adipose tissue (1). PGC-1␣ is highly expressed in tissues with high metabolic demands, such as heart, skeletal muscle, and kidney (1). Ectopic expression of PGC-1␣ was later shown to stimulate the biogenesis of mitochondria by increasing the expression of nuclear respiratory factors 1 and 2 and enhancing the transcriptional activity of nuclear respiratory factor 1 on the promoter for mitochondrial transcription factor A (1). In addition to cold exposure, expression of PGC-1␣ is responsive to various physiological stimuli, such as exercise, caloric restriction, and exposure to lipopolysaccharide (1-4), demonstrating the ability of PGC-1␣ to alter the metabolic state of the cell in response to changes in the cellular or extracellular environment. What has not been examined is the signaling pathway responsible for mitochondrial biogenesis following cellular and mitochondrial injury, particularly oxidative stress.A variety of signaling mechanisms have been proposed to regulate the expression of PGC-1␣ and mitochondrial biogenesis including nitric oxide-soluble guanylate cyclase (5-12), ␤-adren...

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Signaling of Mitochondrial Biogenesis following Oxidant Injury

Rasbach¹,

Schnellmann

2007

Journal of Biological Chemistry

Self Cite

142

View full text Add to dashboard Cite

show abstract

“…The kidney requires high levels of ATP to drive the processes necessary for active tubular transport and is at risk for mitochondrial dysfunction caused by acute ischemia/reperfusion, drugs, toxicants, and diabetes (Ozbek, 2012). It has been demonstrated that recovery of mitochondrial function precedes recovery of cellular structure and function in a renal proximal tubule cell (RPTC) model of oxidant injury (Weinberg et al, 1997;Nowak et al, 1998;Weinberg et al, 2000;Feldkamp et al, 2005). Our laboratory has previously reported that mitochondrial proteins are suppressed up to 144 hours after ischemic acute kidney injury, which indicates that promoting the recovery of mitochondrial function may be a viable therapeutic strategy for the treatment of acute kidney injury (Rasbach and Schnellmann, 2007;Funk and Schnellmann, 2012).…”

Section: Introductionmentioning

confidence: 99%

5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists

Harmon

Wills

McOmish

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT 2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl) propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT 2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney.

show abstract

“…Mitochondrial dysfunction followed by ATP depletion, reduced metabolic functions, and decreases in Na ϩ -K ϩ -ATPase activity and active Na ϩ transport are the major alterations in RPTCs injured by different toxicants (Elfara et al, 1986;Lash and Anders, 1987;Schnellmann, 1988;Lash et al, 1995;Nowak et al, 1998Nowak et al, , 1999Lash et al, 2001). Oxidative stress has been implicated in the mechanism of the renal dysfunction associated with ischemia/reperfusion and the nephrotoxicity of a number of drugs and environmental chemicals, including halocarbons.…”

mentioning

confidence: 99%

Protein Kinase C Mediates Repair of Mitochondrial and Transport Functions after Toxicant-Induced Injury in Renal Cells

Nowak

2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Previously, we have shown that renal proximal tubular cells (RPTCs) recover physiological functions after injury induced by the oxidant tert-butylhydroperoxide (TBHP), but not by the nephrotoxic cysteine conjugate dichlorovinyl-L-cysteine (DCVC). This study examined the role of protein kinase C (PKC) in the repair of RPTC functions after sublethal injury produced by these toxicants. Total PKC activity decreased 65 and 86% after TBHP and DCVC exposures, respectively, and recovered in TBHP-injured but not in DCVC-injured RPTCs. Mitochondrial function, active Na ϩ transport, and Na ϩ -dependent glucose uptake decreased after toxicant exposure and recovered in TBHP-but not in DCVC-injured RPTCs. PKC inhibition decreased the repair of RPTC functions after TBHP injury. PKC activation promoted recovery of mitochondrial function and active Na ϩ transport in TBHP-and DCVC-injured RPTCs but had no effect on recovery of Na ϩ -dependent glucose uptake. We conclude that in RPTCs, 1) total PKC activity decreases after TBHP and DCVC injury and recovers after TBHP but not after DCVC exposure, 2) recovery of PKC activity precedes the return of physiological functions after oxidant injury, 3) PKC inhibition decreases recovery of physiological functions, and 4) PKC activation promotes recovery of mitochondrial function and active Na ϩ transport but not Na ϩ -dependent glucose uptake. These results suggest that the repair of renal functions is mediated through PKC-dependent mechanisms and that cysteine conjugates may inhibit renal repair, in part, through inhibition of PKC signaling.Numerous toxicants can cause renal dysfunction through their ability to induce sublethal injury to renal proximal tubular cells (RPTCs), which results in decreased normal cellular functions without producing cell death and loss. Mitochondrial dysfunction followed by ATP depletion, reduced metabolic functions, and decreases in Na ϩ -K ϩ -ATPase activity and active Na ϩ transport are the major alterations in RPTCs injured by different toxicants (Elfara et al

show abstract

Recovery of cellular functions following oxidant injury

Cited by 30 publications

References 33 publications

Signaling of Mitochondrial Biogenesis following Oxidant Injury

Signaling of Mitochondrial Biogenesis following Oxidant Injury

5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists

Protein Kinase C Mediates Repair of Mitochondrial and Transport Functions after Toxicant-Induced Injury in Renal Cells

Contact Info

Product

Resources

About