Mitochondrial HMG-CoA synthase partially contributes to antioxidant protection in the kidney of stroke-prone spontaneously hypertensive rats.
OBJECTIVE
Increased oxidative stress plays an important role in cardiovascular diseases including hypertension and stroke. Evidence has indicated that ketone bodies could exert antioxidative effects. We explored the role of renal mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS2) expression, a key control site of ketogenesis, in stroke-prone spontaneously hypertensive rats (SHRSPs) and their ancestral hypertensive but stroke-resistant spontaneously hypertensive rats (SHRs).


METHODS
Two groups of SHRSPs were fed a standard chow or standard chow supplemented with clofibrate (an agonist of HMGCS2 promoter), respectively, and SHRs fed with a standard chow were used as controls. The renal levels of HMGCS2, Akt, and phosphorylated protein kinase B (Akt) were measured by western blotting. Malondialdehyde, catalase, superoxide dismutase, and glutathione peroxidase were detected by assay kits.


RESULTS
Compared with SHRs, lower HMGCS2 protein expression, enhanced phosphorylated Akt signal, higher malondialdehyde levels, and higher catalase activity were observed in kidney tissues in SHRSPs (P < 0.05). No differences in superoxide dismutase and glutathione peroxidase activities were observed between SHRSPs and SHRs. Clofibrate treatment significantly upregulated renal HMGCS2 expressions, inhibited phosphorylation of Akt, and decreased malondialdehyde levels and catalase activities in SHRSP kidney tissues (P < 0.05).


CONCLUSIONS
These results demonstrated the difference in HMGCS2 expression and oxidative stress in kidney tissues between SHRSPs and their SHR controls. The enhanced oxidative stress was partly due to the lower HMGCS2 expression regulated possibly by the Akt signaling pathway.
Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Weijie
W
Yi
Ping
P
Fu
Zhiliang
Z
Fan
Hiroaki
H
Aso
Chong
C
Tian
Yi
Y
Meng
Jian
J
Liu
Yukio
Y
Yamori
Yasuo
Y
Nara
Chenjiang
C
Ying
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002374:Catalase / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology* / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000503:physiopathology* / Q000517:prevention & control; D015854:Up-Regulation / Q000187:drug effects
D000959:Antihypertensive Agents; D047495:PPAR gamma; D008315:Malondialdehyde; D002374:Catalase; D006904:Hydroxymethylglutaryl-CoA Synthase; D051057:Proto-Oncogene Proteins c-akt; D002994:Clofibrate