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Implications of hyperhomocysteinemia in glomerular sclerosis in hypertension
Ningjun Li1, Ya-Fei Chen, Ai-Ping Zou
1Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Insights
Elevated homocysteine (hHcys) contributes to kidney damage in hypertension, independent of blood pressure. This study shows hHcys causes glomerulosclerosis, suggesting it
Area of Science:
- Nephrology
- Cardiovascular Research
- Metabolic Diseases
Background:
- Hyperhomocysteinemia (hHcys) is a recognized cardiovascular risk factor.
- The role of hHcys in hypertension-related target organ damage, specifically glomerulosclerosis, is not well understood.
Purpose of the Study:
- To investigate the potential role of hHcys in the development of glomerulosclerosis in hypertensive rats.
- To determine if hHcys independently contributes to glomerular damage in the context of hypertension.
Main Methods:
- Utilized Dahl salt-sensitive (DS) hypertensive rats and Sprague-Dawley rats.
- Measured plasma total homocysteine (tHcys) using high-performance liquid chromatography.
- Administered desferrioxamine to assess its effect on tHcys and glomerulosclerosis.
- Induced hHcys in Sprague-Dawley rats using methionine and evaluated renal and vascular changes.
Main Results:
- DS rats on a high-salt diet showed significantly increased plasma tHcys and glomerulosclerosis.
- Desferrioxamine treatment normalized plasma tHcys and attenuated glomerular damage in DS rats.
- Methionine-induced hHcys in Sprague-Dawley rats led to increased urinary protein excretion and glomerulosclerosis, without altering arterial pressure.
- Vascular sclerotic changes were observed in the aorta of rats with induced hHcys.
Conclusions:
- Elevated plasma homocysteine is implicated in the pathogenesis of glomerular damage associated with hypertension.
- hHcys may act as an independent risk factor for glomerulosclerosis, irrespective of elevated blood pressure.
- Targeting homocysteine levels could be a potential therapeutic strategy for preventing hypertensive kidney disease.
Abstract:
Hyperhomocysteinemia (hHcys) has been recognized as a new risk factor for cardiovascular diseases independent of plasma lipid levels or other factors. However, it remains unknown whether hHcys is implicated in the target organ damages associated with hypertension. The present study first examined the possible role of hHcys in the development of glomerulosclerosis in Dahl salt-sensitive (DS) hypertensive rats. High-performance liquid chromatography showed that plasma total homocysteine (tHcys) concentration was 7.64 +/- 0.29 micromol/L in conscious DS rats on a low salt (0.4% NaCl) diet, which was higher than 5.23 +/- 0.25 micromol/L in Dahl salt-resistant normotensive rats. When these rats were exposed to a high salt (4% NaCl) diet, plasma tHcys markedly increased in DS rats (14.7 +/-1.31 micromol/L) but not in Dahl salt-resistant rats (5.34 +/- 0.54 micromol/L). An iron chelater, desferrioxamine (0.3 mg/kg IV per day), completely normalized high salt--induced elevations of plasma tHcys and significantly attenuated the sclerotic changes in the glomeruli in DS rats. To further determine whether hHcys has an independent effect in the development of glomerulosclerosis, Sprague-Dawley rats were fed drinking water containing methionine (1 g/kg per day) for 6 weeks to produce hHcys. In these rats, plasma tHcys increased to 12.5 +/- 1.9 micromol/L (versus 6.1 +/- 2.6 micromol/L in control rats), and the aorta exhibited typical sclerotic changes, but arterial pressure was not altered. Urinary protein excretion increased to 52 +/- 2 mg/24 hours (versus 17 +/- 2 mg/24 hours in control rats), and the glomerular mesangium was expanded with glomerular hypercellularity, capillary collapse, and fibrous deposition in the rats with hHcys. These results suggest that elevated plasma homocysteine may be an important pathogenic factor for glomerular damage in hypertension independent of arterial pressure.