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Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha
Cheol Whee Park1, Hyeong Wook Kim, Seung Hyun Ko
1Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, 62, Yoido-Dong, Youngdeungpo-Ku, Seoul, Korea 150-713.
Abstract:
Peroxisome proliferator-activated receptor (PPAR)alpha, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at determining the role of PPARalpha in the pathogenesis of diabetic nephropathy using PPARalpha-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPARalpha-knockout and wild-type mice. Diabetic PPARalpha-knockout and wild-type mice developed elevated fasting blood glucose (P < 0.001) and HbA1c levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPARalpha-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPARalpha immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPARalpha-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPARalpha-knockout and wild-type mice and diabetic PPARalpha wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-beta1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPARalpha agonist fenofibrate. Taken together, PPARalpha deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPARalpha agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy.
Insights
Peroxisome proliferator-activated receptor (PPAR)alpha deficiency worsens diabetic kidney disease by increasing inflammation and extracellular matrix. PPARalpha agonists may offer a therapeutic strategy for diabetic nephropathy.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Peroxisome proliferator-activated receptor (PPAR)alpha is crucial for lipid and glucose metabolism, with high kidney expression.
- Diabetic nephropathy is a major complication of diabetes, characterized by kidney damage.
Purpose of the Study:
- To investigate the role of PPARalpha in the development of diabetic nephropathy.
- To evaluate the impact of PPARalpha deficiency on renal function and pathology in a mouse model of diabetes.
Main Methods:
- Utilized PPARalpha-knockout and wild-type mice subjected to streptozotocin-induced diabetes.
- Assessed renal function, histopathology, and molecular markers after 16 weeks of hyperglycemia.
- Conducted in vitro studies using cultured murine mesangial cells exposed to high glucose.
Main Results:
- Diabetic PPARalpha-knockout mice exhibited more severe albuminuria, glomerular sclerosis, and mesangial expansion compared to wild-type mice.
- PPARalpha deficiency led to increased serum free fatty acids, triglycerides, renal type IV collagen, osteopontin, macrophage infiltration, and glomerular apoptosis.
- High glucose in vitro increased extracellular matrix components and leukocyte adhesion, which was reduced by a PPARalpha agonist.
Conclusions:
- PPARalpha deficiency exacerbates diabetic nephropathy through enhanced extracellular matrix deposition, inflammation, and altered lipid metabolism.
- PPARalpha agonists demonstrate potential as therapeutic agents for managing type 1 diabetic nephropathy.
