The long-term goal of this research is to elucidate the mechanisms that regulate the recovery of physiological functions in renal proximal tubular cells (RPTC) following toxicant-induced injury. Kidney exposure to a variety of drugs and toxicants results in acute renal failure (ARF). RPTC are the major target for many nephrotoxicants and the recovery of the kidney following injury occurs through the regeneration of the non-injured and repair of sublethally-injured RPTC. Therapeutic strategies used to treat ARF are often unsuccessful due to the poor understanding of the mechanisms regulating RPTC regeneration and repair. The goal of this proposal is to elucidate the role of 3 major isozymes of protein kinase C (PKCx, PKCo, and PKCc) in the repair of RPTC functions following toxicant-induced injury. In our in vitro model of cell regeneration and repair (primary cultures of rabbit RPTC grown in improved culture conditions) RPTC recover their mitochondrial and transport functions following exposure to an oxidant (tertbutylhydroperoxide, TBHP) but not a halocarbon (dichlorovinyl-L-cysteine, DCVC). Inhibition of these functions in sublethally-injured RPTC following TBHP exposure is accompanied with the decrease in protein kinase C (PKC) activity. Activation of PKC prior to TBHP exposure accelerates recovery while inhibition of PKC prevents the return of RPTC functions. Lack of RPTC repair after DCVC exposure is accompanied by sustained inhibition of PKC activity and PKC activation prior to DCVC exposure promotes recovery of RPTC functions. Therefore, the central hypothesis of this proposal is that PKCa, PKC6, and PKCc play a pivotal role in the repair of mitochondrial and transport functions of RPTC following toxicant injury and that the recovery of these functions depends on re-establishment of PKC-mediated signaling.
Specific Aim I will examine the alterations in the activity, protein levels and subcellular localization of major PKC isozymes after toxicant injury and during recovery.
Specific Aim II will demonstrate that the recovery of mitochondrial and transport functions following toxicant injury is mediated through PKCa, PKCS and/or PKCe.
Specific Aim III will identify pathways that are involved in regulation of recovery of RPTC functions by PKC. Completion of these aims will result in a better understanding of the role of PKC isozymes in the repair of RPTC functions and may help to identify agents that protect against ARF or accelerate recovery from ARF.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Star, Robert A
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University of Arkansas for Medical Sciences
Schools of Pharmacy
Little Rock
United States
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Nowak, Grazyna; Bakajsova-Takacsova, Diana (2018) Protein kinase C? targets respiratory chain and mitochondrial membrane potential but not F0 F1 -ATPase in renal cells injured by oxidant. J Cell Biochem 119:9394-9407
Nowak, Grazyna; Takacsova-Bakajsova, Diana; Megyesi, Judit (2017) Deletion of protein kinase C-? attenuates mitochondrial dysfunction and ameliorates ischemic renal injury. Am J Physiol Renal Physiol 312:F109-F120
Nowak, Gra?yna; Bakajsova, Diana (2015) Protein kinase C-? interaction with F0F1-ATPase promotes F0F1-ATPase activity and reduces energy deficits in injured renal cells. J Biol Chem 290:7054-66
Nowak, Gra?yna; Bakajsova, Diana (2013) Assessment of mitochondrial functions and cell viability in renal cells overexpressing protein kinase C isozymes. J Vis Exp :
Nowak, Grazyna; Soundararajan, Sridharan; Mestril, Ruben (2013) Protein kinase C-? interaction with iHSP70 in mitochondria promotes recovery of mitochondrial function after injury in renal proximal tubular cells. Am J Physiol Renal Physiol 305:F764-76
Nowak, Grazyna; Bakajsova, Diana; Hayes, Corey et al. (2012) ?-Tocotrienol protects against mitochondrial dysfunction and renal cell death. J Pharmacol Exp Ther 340:330-8
Nowak, Grazyna; Bakajsova, Diana (2012) Protein kinase C-? activation promotes recovery of mitochondrial function and cell survival following oxidant injury in renal cells. Am J Physiol Renal Physiol 303:F515-26
Nowak, Grazyna; Bakajsova, Diana; Samarel, Allen M (2011) Protein kinase C-epsilon activation induces mitochondrial dysfunction and fragmentation in renal proximal tubules. Am J Physiol Renal Physiol 301:F197-208
Nowak, Grazyna; Clifton, Ginger L; Bakajsova, Diana (2008) Succinate ameliorates energy deficits and prevents dysfunction of complex I in injured renal proximal tubular cells. J Pharmacol Exp Ther 324:1155-62
Shaik, Zabeena P; Fifer, E Kim; Nowak, Grazyna (2008) Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury. Am J Physiol Renal Physiol 294:F423-32

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