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Internephron heterogeneity of growth factors and sclerosis--modulation of platelet-derived growth factor by
R Tanaka1, K Sugihara, A Tatematsu
1Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Abstract:
We studied the early phase after 5/6 nephrectomy in Munich-Wistar rats to determine whether treatment with angiotensin II receptor antagonist (AIIRA) modulates the expression of platelet-derived growth factor (PDGF) mRNA and its protein among the glomeruli which are undergoing progressive hypertrophy and sclerosis. Average PDGF-B immunohistochemistry staining score (IHS, 0 to 3 scale) in glomeruli and PDGF-B chain mRNA from kidneys were both increased in 5/6 nephrectomy rats (N = 6) versus age-matched normal (N = 5) at week 4, when glomeruli were at early stages of sclerosis (IHS, 0.81 +/- 0.12 vs. 0.19 +/- 0.05; sclerosis index, S.I., 0 to 4 scale: 0.41 +/- 0.04 vs. 0.05 +/- 0.01, both P < 0.05). AIIRA (80 mg/liter drinking water, N = 6) started at time of 5/6 nephrectomy prevented the development of sclerosis (S.I. 0.08 +/- 0.03) and decreased PDGF-B protein (IHS 0.22 +/- 0.08, both P = NS vs. normal), and PDGF-B chain mRNA. In contrast, triple therapy (TRX; hydralazine, reserpine and hydrochlorothiazide, N = 5) in doses which controlled systemic blood pressure resulted in intermediate level of glomerulosclerosis at this early time point of progressive injury. Concurrently, TRX failed to affect the expression of PDGF-B protein (IHS 0.86 +/- 0.19) or its mRNA expression. The PDGF-B distribution was not uniform amongst the glomeruli with varying stages of sclerosis. There was a strong correlation in individual glomeruli of increased PDGF-B staining with early sclerotic changes (P < 0.01), with the disappearance of this correlation in glomeruli with advanced sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Angiotensin II receptor antagonist (AIIRA) treatment in rats with reduced kidney mass prevented glomerulosclerosis and decreased platelet-derived growth factor (PDGF). This suggests AIIRA may be a therapeutic target for kidney disease progression.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Kidney injury after 5/6 nephrectomy leads to progressive hypertrophy and sclerosis.
- Platelet-derived growth factor (PDGF) is implicated in glomerular sclerosis.
Purpose of the Study:
- To investigate the effect of angiotensin II receptor antagonist (AIIRA) on PDGF expression in early-stage kidney injury.
- To compare AIIRA with triple therapy (TRX) in modulating PDGF and preventing glomerulosclerosis.
Main Methods:
- Munich-Wistar rats underwent 5/6 nephrectomy.
- Rats were treated with AIIRA or triple therapy (TRX).
- PDGF-B mRNA and protein expression, glomerulosclerosis index, and immunohistochemistry staining were assessed.
Main Results:
- 5/6 nephrectomy increased glomerular PDGF-B mRNA and protein, correlating with early sclerosis.
- AIIRA treatment prevented sclerosis and reduced PDGF-B expression.
- TRX controlled blood pressure but did not affect PDGF-B expression or significantly alter sclerosis.
Conclusions:
- AIIRA effectively reduces PDGF-B expression and prevents early glomerulosclerosis in a rat model of reduced kidney mass.
- PDGF-B plays a role in the early stages of glomerulosclerosis.
- AIIRA shows potential as a therapeutic strategy for chronic kidney disease.