Abstract
The vast increase of chronic kidney disease (CKD) has attracted considerable attention worldwide, and the development of a novel therapeutic option against a representative kidney disease that leads to CKD, mesangial proliferative glomerulonephritis (MsPGN) would be significant. Peroxisome proliferator-activated receptor α (PPARα), a member of the steroid/nuclear receptor superfamily, is known to perform various physiological functions. Recently, we reported that PPARα in activated mesangial cells exerted anti-inflammatory effects and that the deficiency of PPARα resulted in high susceptibility to glomerulonephritis. To investigate whether PPARα activation improves the disease activity of MsPGN, we examined the protective effects of a PPARα agonist, clofibrate, in a well-established model of human MsPGN, anti-Thy1 nephritis, for the first time. This study demonstrated that pretreatment with clofibrate (via a 0.02% or 0.1% clofibrate-containing diet) continuously activated the glomerular PPARα, which outweighed the PPARα deterioration associated with the nephritic process. The PPARα activation appeared to suppress the NF-κB signaling pathway in glomeruli by the induction of IκBα, resulting in the reduction of proteinuria and the amelioration of the active inflammatory pathologic glomerular changes. These findings suggest the antinephritic potential of PPARα-related medicines against MsPGN. PPARα-related medicines might be useful as a treatment option for CKD.
Highlights
The vast increase in chronic kidney disease (CKD) has attracted considerable attention worldwide, since CKD is one of the most important risk factors for cardiovascular events, the induction of kidney replacement therapies, and death [1]
To investigate whether Peroxisome proliferator-activated receptor α (PPARα) activation improves the disease activity of mesangial proliferative glomerulonephritis (MsPGN), we examined the protective effects of a PPARα agonist, clofibrate, in a well-established model of human MsPGN, anti-Thy1 nephritis, for the first time
To obtain basic evidence concerning the beneficial potential of PPARα ligand against MsPGN, we examined the glomerular protective effects of a PPARα agonist, clofibrate, in a well-established rat model of human MsPGN, antiThy1 nephritis
Summary
The vast increase in chronic kidney disease (CKD) has attracted considerable attention worldwide, since CKD is one of the most important risk factors for cardiovascular events, the induction of kidney replacement therapies, and death [1]. Among many types of primary kidney disease, mesangial proliferative glomerulonephritis (MsPGN) including IgA nephropathy is a representative proteinuric kidney disease that leads to CKD [2, 3]. Various medications such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, fish oil, statins, hydroxymethylglutarylCoA reductase inhibitors, immunosuppressive therapy, antiplatelets, and anticoagulants have been proposed; it remains difficult to control the nephritic activity associated with severe inflammatory pathologic glomerular changes [4]. Peroxisome proliferator-activated receptor α (PPARα), a member of the steroid/nuclear receptor superfamily of ligand-dependent transcription factors, is known to perform various physiological functions, including the maintenance of lipid and glucose homeostasis, the regulation of cell
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