Increased renal methylglyoxal formation with down-regulation of PGC-1α-FBPase pathway in cystathionine γ-Lyase knockout mice

Ashley A. Untereiner, Arti Dhar, Jianghai Liu, Lingyun Wu

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We have previously reported that hydrogen sulfide (H 2S), a gasotransmitter and vasodilator has cytoprotective properties against methylglyoxal (MG), a reactive glucose metabolite associated with diabetes and hypertension. Recently, H 2S was shown to up-regulate peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, a key gluconeogenic regulator that enhances the gene expression of the rate-limiting gluconeogenic enzyme, fructose-1,6-bisphosphatase (FBPase). Thus, we sought to determine whether MG levels and gluconeogenic enzymes are altered in kidneys of 6-22 week-old cystathionine γ-lyase knockout (CSE -/-; H 2S-producing enzyme) male mice. MG levels were determined by HPLC. Plasma glucose levels were measured by an assay kit. Q-PCR was used to measure mRNA levels of PGC-1α and FBPase-1 and -2. Coupled-enzymatic assays were used to determine FBPase activity, or triosephosphate levels. Experimental controls were either age-matched wild type mice or untreated rat A-10 cells. Interestingly, we observed a significant decrease in plasma glucose levels along with a significant increase in plasma MG levels in all three age groups (6-8, 14-16, and 20-22 week-old) of the CSE -/- mice. Indeed, renal MG and triosephosphates were increased, whereas renal FBPase activity, along with its mRNA levels, were decreased in the CSE -/- mice. The decreased FBPase activity was accompanied by lower levels of its product, fructose-6-phosphate, and higher levels of its substrate, fructose-1,6-bisphosphate in renal extracts from the CSE -/- mice. In agreement, PGC-1α mRNA levels were also significantly down-regulated in 6-22 week-old CSE -/- mice. Furthermore, FBPase-1 and -2 mRNA levels were reduced in aorta tissues from CSE -/- mice. Administration of NaHS, a H 2S donor, increased the gene expression of PGC-1α and FBPase-1 and -2 in cultured rat A-10 cells. In conclusion, overproduction of MG in CSE -/- mice is due to a H 2S-mediated down-regulation of the PGC-1α-FBPase pathway, further suggesting the important role of H 2S in the regulation of glucose metabolism and MG generation.

Original languageEnglish (US)
Article numbere29592
JournalPLoS One
Volume6
Issue number12
DOIs
StatePublished - Dec 22 2011
Externally publishedYes

Fingerprint

Cystathionine
cystathionine
Fructose-Bisphosphatase
Pyruvaldehyde
Lyases
lyases
Knockout Mice
fructose
Down-Regulation
kidneys
Kidney
mice
Glucose
Messenger RNA
antineoplaston A10
glucose
Plasmas
Gene expression
Rats
Assays

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Increased renal methylglyoxal formation with down-regulation of PGC-1α-FBPase pathway in cystathionine γ-Lyase knockout mice. / Untereiner, Ashley A.; Dhar, Arti; Liu, Jianghai; Wu, Lingyun.

In: PLoS One, Vol. 6, No. 12, e29592, 22.12.2011.

Research output: Contribution to journalArticle

Untereiner, Ashley A. ; Dhar, Arti ; Liu, Jianghai ; Wu, Lingyun. / Increased renal methylglyoxal formation with down-regulation of PGC-1α-FBPase pathway in cystathionine γ-Lyase knockout mice. In: PLoS One. 2011 ; Vol. 6, No. 12.
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