Transgenic expression of proximal tubule peroxisome proliferator-activated receptor-alpha in mice confers protection during acute kidney injury.
Our previous studies suggest that peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a critical role in regulating fatty acid beta-oxidation in kidney tissue and this directly correlated with preservation of kidney morphology and function during acute kidney injury. To further study this, we generated transgenic mice expressing PPARalpha in the proximal tubule under the control of the promoter of KAP2 (kidney androgen-regulated protein 2). Segment-specific upregulation of PPARalpha expression by testosterone treatment of female transgenic mice improved kidney function during cisplatin or ischemia-reperfusion-induced acute kidney injury. Ischemia-reperfusion injury or treatment with cisplatin in wild-type mice caused inhibition of fatty-acid oxidation, reduction of mitochondrial genes of oxidative phosphorylation, mitochondrial DNA, fatty-acid metabolism, and the tricarboxylic acid cycle. Similar injury in testosterone-treated transgenic mice resulted in amelioration of these effects. Similarly, there were increases in the levels of 4-hydroxy-2-hexenal-derived lipid peroxidation products in wild-type mice, which were also reduced in the transgenic mice. Similarly, necrosis of the S3 segment was reduced in the two injury models in transgenic mice compared to wild type. Our results suggest proximal tubule PPARalpha activity serves as a metabolic sensor. Its increased expression without the use of an exogenous PPARalpha ligand in the transgenic mice is sufficient to protect kidney function and morphology, and to prevent abnormalities in lipid metabolism associated with acute kidney injury.
Li
Shenyang
S
Division of Nephrology, Departments of Internal Medicine and Immunology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.
Nagothu
Kiran K
KK
Desai
Varsha
V
Lee
Taewon
T
Branham
William
W
Moland
Carrie
C
Megyesi
Judit K
JK
Crew
Mark D
MD
Portilla
Didier
D
D000208:Acute Disease; D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D002945:Cisplatin; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007668:Kidney / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*
D005230:Fatty Acids, Nonesterified; D047493:PPAR alpha; D002945:Cisplatin