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Podocyte injury and glomerulosclerosis in hyperhomocysteinemic rats
Fan Yi1, Elisabete A dos Santos, Min Xia
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Insights
Elevated homocysteine (Hcys) levels cause early glomerular injury, linked to podocyte damage and altered protein expression. This occurs even before significant changes in kidney function are detected.
Area of Science:
- Nephrology
- Pathophysiology
- Molecular Biology
Background:
- Hyperhomocysteinemia (hHcys) is known to cause glomerular injury.
- The precise timing and mechanisms of hHcys-induced glomerular damage remain unclear.
Purpose of the Study:
- To determine the temporal development of glomerular injury during hHcys.
- To investigate the role of podocyte injury in glomerulosclerosis progression due to hHcys.
Main Methods:
- Uninephrectomized rats were administered methionine to induce hHcys.
- The study monitored plasma Hcys, urinary albumin excretion, and performed morphological and immunofluorescence analyses over time.
Main Results:
- Plasma Hcys increased within 1 week, but creatinine clearance remained unchanged for 6 weeks.
- Urinary albumin excretion and mesangial expansion appeared by week 2.
- Podocyte effacement, reduced podocin/nephrin expression, and increased alpha-actinin-4 were observed during hHcys.
Conclusions:
- Elevated plasma Hcys is an early pathogenic factor in glomerular injury.
- Podocyte injury and altered expression of podocyte-associated proteins contribute to hHcys-induced glomerulosclerosis.
Background/Aims:
We previously reported that increase in plasma homocysteine (Hcys) levels by a 6-week methionine treatment produced remarkable glomerular injury. However, the mechanism by which hyperhomocysteinemia (hHcys) produces glomerular injury remains unknown. The present study was to observe when glomerular injury happens during hHcys and to explore the possible role of podocyte injury in the progression of glomerulosclerosis associated with hHcys.
Methods:
Uninephrectomized Sprague-Dawley rats treated with methionine were used to examine the time course of glomerular injury induced by hHcys.
Results:
Creatinine clearance was not different until rats were treated with methionine for 6 weeks, although plasma Hcys levels significantly increased at the 1st week of methionine treatment. However, urinary albumin excretion increased at the 2nd week of methionine treatment. Morphological examinations showed that mesangial expansion occurred at the 2nd week and podocyte effacement was also observed as processed glomerular damage during hHcys. Immunofluorescence analyses demonstrated that podocin and nephrin expressions were reduced, while alpha-actinin-4 increased during hHcys.
Conclusions:
Increased plasma Hcys level is an important pathogenic factor resulting in glomerular injury even in the very early time of hHcys. These pathogenic effects of Hcys are associated with podocyte injury and changed expression and distribution of podocyte-associated proteins.
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