PMID- 23691217
OWN - NLM
STAT- MEDLINE
DCOM- 20140107
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 5
DP  - 2013
TI  - Peroxisome proliferator-activated receptor delta agonist, HPP593, prevents renal 
      necrosis under chronic ischemia.
PG  - e64436
LID - 10.1371/journal.pone.0064436 [doi]
LID - e64436
AB  - The Goldblatt's 2 kidney 1 clip (2K1C) rat animal model of renovascular 
      hypertension is characterized by ischemic nephropathy of the clipped kidney. 2K1C 
      rats were treated with a specific peroxisome proliferator-activated receptor delta 
      (PPARdelta) agonist, HPP593. Clipped kidneys from untreated rats developed tubular 
      and glomerular necrosis and massive interstitial, periglomerular and perivascular 
      fibrosis. HPP593 kidneys did not exhibit any histochemical features of necrosis; 
      fibrotic lesions were present only in perivascular areas. Necrosis in the 
      untreated clipped kidneys was associated with an increased oxidative stress, up 
      regulation and mitochondrial translocation of the pro-death protein BNIP3 
      specifically in tubules. In the kidneys of HPP593-treated rats oxidative stress 
      was attenuated and BNIP3 protein decreased notably in the mitochondrial fraction 
      when compared to untreated animals. In untreated clipped kidneys, mitochondria 
      were dysfunctional as revealed by perturbations in the levels of MCAD, COXIV, 
      TFAM, and Parkin proteins and AMPK activation, while in HPP593-treated rats these 
      proteins remained at the physiological levels. Nuclear amounts of oxidative 
      stress-responsive proteins, NRF1 and NRF2 were below physiological levels in 
      treated kidneys. Mitochondrial biogenesis and autophagy were inhibited similarly 
      in both treated and untreated 2K1C kidneys as indicated by a decrease in PGC1-alpha 
      and deficiency of the autophagy-essential proteins LC3-II and ATG5. However, 
      HPP593 treatment resulted in increased accumulation of p62 protein, an autophagic 
      substrate and an enhancer of NRF2 activity. Therefore, inhibition of BNIP3 
      activation by the preservation of mitochondrial function and control of oxidative 
      stress by PPARdelta is the most likely mechanism to account for the prevention of 
      necrotic death in the kidney under conditions of persistent ischemia.
FAU - Fedorova, Larisa V
AU  - Fedorova LV
AD  - Department of Medicine, The University of Toledo School of Medicine, Toledo, 
      Ohio, United States of America. Larisa.fedorova@utoledo.edu
FAU - Sodhi, Komal
AU  - Sodhi K
FAU - Gatto-Weis, Cara
AU  - Gatto-Weis C
FAU - Puri, Nitin
AU  - Puri N
FAU - Hinds, Terry D Jr
AU  - Hinds TD Jr
FAU - Shapiro, Joseph I
AU  - Shapiro JI
FAU - Malhotra, Deepak
AU  - Malhotra D
LA  - eng
GR  - R01 HL109015/HL/NHLBI NIH HHS/United States
GR  - U01 HL071556/HL/NHLBI NIH HHS/United States
GR  - 263-MA-707136-1/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130515
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (DNA Primers)
RN  - 0 (PPAR delta)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Chronic Disease
MH  - DNA Primers
MH  - Ischemia/*pathology
MH  - Kidney/*blood supply
MH  - Male
MH  - Necrosis/*prevention & control
MH  - PPAR delta/*agonists
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC3654981
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/05/22 06:00
MHDA- 2014/01/08 06:00
PMCR- 2013/05/15
CRDT- 2013/05/22 06:00
PHST- 2012/11/29 00:00 [received]
PHST- 2013/04/15 00:00 [accepted]
PHST- 2013/05/22 06:00 [entrez]
PHST- 2013/05/22 06:00 [pubmed]
PHST- 2014/01/08 06:00 [medline]
PHST- 2013/05/15 00:00 [pmc-release]
AID - PONE-D-12-37498 [pii]
AID - 10.1371/journal.pone.0064436 [doi]
PST - epublish
SO  - PLoS One. 2013 May 15;8(5):e64436. doi: 10.1371/journal.pone.0064436. Print 2013.