Hepatic HMG-CoA reductase gene expression during the course of puromycin-induced nephrosis.

Abstract

Increased production and depressed catabolism of lipoproteins play major roles in the pathogenesis of hypercholesterolemia of nephrotic syndrome (NS). However, the effect, if any, of NS on cholesterol biosynthetic capacity is uncertain. We examined the gene expression of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR, the rate limiting step in cholesterol biosynthesis) during the induction and chronic phase of puromycin (PAN)-induced NS in rats. The rats were randomized to NS (given i.p. puromycin aminonucleoside 130 mg/kg on day 1 and 60 mg/kg on day 14) and placebo-treated control groups. Subgroups of animals were sacrificed at days 5, 10, 20 and 30. The liver was harvested between 7 and 9 p.m. for measurements of HMG-CoAR and actin mRNAs, HMG-CoAR enzymatic activity and microsomal cholesterol concentration. In separate experiments, subgroups of animals with chronic NS (day 30) were studied in fed and 20-hour fasting states. A marked but transient rise in hepatic HMG-CoAR mRNA and HMG-CoAR enzymatic activity was observed following the onset and exacerbation of proteinuria within a few days after each puromycin injection. On each occasion, HMG-CoAR fell to the baseline level despite persistent severe hypercholesterolemia. In an attempt to examine the possible acute effect of PAN per se, experiments were repeated before and at short intervals (8 and 24 hr) after puromycin injection when proteinuria was absent and the drug exposure prominent. The HMG-CoAR mRNA and activity were virtually unchanged during this period, suggesting the lack of an acute effect of puromycin. Twenty-hour fasting led to a marked rise in HMG-CoAR mRNA and activity in animals with chronic NS but not in the controls. Microsomal cholesterol remained unchanged and comparable in the two groups at all points. Thus, the marked but transient rise in hepatic HMG-CoAR gene expression observed during the induction phase and with fasting during the chronic phase of PAN-induced NS may contribute to the generation and maintenance of hypercholesterolemia in this animal model.

• Authors: N D Vaziri, K H Liang
• Journal: Kidney international (Kidney Int) Vol. 48 Issue 6 Pg. 1979-85 (Dec 1995) ISSN: 0085-2538 [Print] United States
• PMID: 8587261 (Publication Type: Journal Article)

Chemical References

• RNA, Messenger
• Puromycin
• Creatinine
• Hydroxymethylglutaryl CoA Reductases
• Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent

Topics

• Analysis of Variance
• Animals
• Blotting, Northern
• Creatinine (metabolism)
• Gene Expression (physiology)
• Hydroxymethylglutaryl CoA Reductases (genetics, metabolism)
• Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent
• Hypercholesterolemia (enzymology, etiology)
• Male
• Nephrosis (chemically induced, complications, enzymology)
• Puromycin
• RNA, Messenger (metabolism)
• Random Allocation
• Rats
• Rats, Sprague-Dawley