| Abstract|| |
The pharmacology of the perioxisome proliferators activated receptor PRAR ligands is summarized. The alpha, delta (beta) and gamma receptors occur in vascular walls and on macrophages suggesting that their ligands can be used to modify atherosclerosis and other forms of vascular disease. Furthermore, gamma-ligands exert an anti-inflammatory effect on macrophages. Troglitazone has been used to protect against glomerulosclerosis in rats. The thiazolidinediones (TZDs) could be important adjunct therapy for lupus glomerulonephritis.
Keywords: Perioxisome proliferators, Receptors, Lupus, Glomerulonephritis, Glomerulosclerosis.
|How to cite this article:|
Wardle E N. PPAR: Receptors that Regulate Inflammation. Saudi J Kidney Dis Transpl 2004;15:1-6
| Introduction|| |
Perioxisome proliferator activated receptors (PPARs) are transcription factors and members of the nuclear receptor superfamily. , In mammalian cells there are PPARα which play a critical role in cellular uptake and β-oxidation of fatty acids, , PPARδ/β  and PPARγ , which modify inflammatory responses. , Leukotriene B4 (LTB4), polyunsaturated fatty acids and the hypolipidaemic agents, the fibrates, are selective PPARα agonists. Carbaprostacyclin is reported to selectively activate PPARδ. The cyclopentenone prostaglandin that is derived from PGD2 and called 15dPGJ2 and thiazolidinedione antidiabetic compounds are PPARγ ligands. The relevance of these receptors to inflammation was appreciated when PPARα was found to respond to LTB4. Activation of PPARα inhibits the inflammatory action of eicosanoids by augmenting the hepatic enzymes required for their metabolism. Treatment of activated macrophages with PPARα and γ agonists causes apoptosis b1 interfering with NF-kB survival pathway.
Details of how PPAR heterodimerises with the retinoic acid receptor (RAR) to bind the perioxisome proliferator response elements (PPREs) upstream of genes that are activated or inhibited is in reviews. ,, PPARα are expressed in tissues with a high rate of fatty acid catabolism like liver, heart, muscle and kidneys. PPARγ are sited in adipose tissue, the mammary glands and the gut. They also occur in immune cell types like macrophages, mesangial cells, synoviocytes and chondrocytes, T and B lymphocytes. Stimulation of PPARγ leads to inhibition of iNOS and Cox-2 and inhibition of release of cytokines IL-1, IL-2, IL-6 and TNFa. Hence such ligands can control chronic inflammation like that of rheumatoid arthritis. 
What might the PPARs contribute to Nephrology?
The presence of PPARα, PPARδ  and PPARD in cells of the vessel wall, such as endothelial cells, smooth muscle cells and macrophages suggests that their ligands will have anti-atherosclerotic potential. , [Table - 1] summarizes the available therapeutic ligands.
PPARα is involved in the regulation of endothelial cell inflammatory responses. Ligands for PPARα and PPARγ modulate the recruitment of leucocytes and their adhesion to endothelial cells, regulate production of cytokines and endothelial and vascular smooth muscle cells, and affect lipid homeostasis of monocyte-macrophages that would be involved in vasculitis or atheroma. The proinflammatory adhesion molecules that appear on endothelial cells are downregulated by PPARγ ligands,  as well as PPARα.  Their action is via repression of the transcription factors NF-kB and AP-1  and so ICAM-1 and VCAM-1 are not expressed. PPARα inhibit thrombin induced expression of endothelin-1, and PPARα inhibit expression of I1-6 and tissue factor on endothelial cells, smooth muscle cells and macrophages. PPARγ ligands like glitazones inhibit formation of monocyte recruiting chemokine MCP-1, and inhibit expression of CCR2 on monocytes so that recruitment is thwarted.
PPARγ promote cholesterol accumulation in macrophages by upregulation of genes for cholesterol accumulation like scavenger receptors A and CD36, and yet they induce the ABC.1 transporter cholesterol efflux pump.  Hence the overall action could be complex. Fortunately rosiglitazone improved atherosclerosis in LDL receptor knock-out mice, and troglitazone reduced development of atherosclerosis in Watanabe heritable hyperlipidemic rabbits.  PPARγ increases CD36 expression, a promoter of lipid accumulation, but it decreases scavenger receptors-A and the net effect is no foam cell formation. PPARγ will inhibit T cells that might contribute to atherosclerosis and certainly to vasculitis. 
The hypolipidaemic fibrates activate PPARα across species. Treatment of patients lowers their triglycerides and induces moderate elevation of HDL. The PPARγ ligands like the TZDs help to regulate glucose and lipid homeostasis. Mutation in the ligand binding domains of PPARγ causes a syndrome of insulin resistance, diabetes and hypertension.
Macrophages derived from monocytes are important in glomerular inflammation, formation of crescents and glomerulosclerosis, and in the induction of tubulointerstitial fibrosis of the kidneys. Monocytes do not express PPARγ but it is induced by ligation with ICAM-3, which occurs on other leucocytes. Activated monocytes display PPARγ and in them it helps induction of Cox-2.  As indicated, PPARγ regulates the scavenger receptor CD36 which helps lipid accumulation in macrophages, and, as readers will know parallels between atherosclerosis and glomerulosclerosis have proved to be valid. PPARα is present in undifferentiated monocytes and in macrophages. Ligands for PPARγ cause apoptosis of activated macrophages.  Clearly there ought to be therapeutic potential here. Also PPARγ ligands inhibit macrophage inflammatory responses,  especially in a murine system,  but one must note that the presence of IFNγ might prevent PPARγ ligands from completely suppressing macrophage proinflammatory cytokines!  Moreover the latter study revealed that there were differences in potency of the PPARγ ligands attributable to differences in their PPARγ binding site affinities, and the effectiveness of the ligands did depend on the nature of the inciting stimulus. One will note furthermore that nitric oxide donors can switch monocyte-macrophages from a pro- to an anti-inflammatory phenotype by activation of PPAR as shown by EMSAs.  In particular a PPARγ responsive gene product attenuates the respiratory burst of macrophages. 
The anti-inflammatory effect of PPARγ ligands directed at macrophages is impressive,  albeit one must be aware that all publications do not concur.  PPARγ ligands (i) decrease the output of vital cytokines like I1-1β , I1-6, TNFa and I1-12, (ii) decrease the expression of iNOS by macrophages, (iii) decrease the formation of metalloproteinases.  There can be induction of macrophage apoptosis.
PPAR Ligands and Renal Pathology
In view of these actions one will not be surprised that the PPARγ agonist troglitazone confers protection against glomerulosclerosis in rats with 5/6 nephrectomy.  There was reduction of glomerular cell proliferation associated with a reduction of glomerular macrophages which would mean decreased ROS related injury. TGFβ was decreased in glomerular and tubular epithelial cells. So was the expression of PAI-1 which could reflect the suppressive action of PPARγ on NF-kB and AP-I.  We know too that PPARα and γ repress TNFa induced expression of selections required for the recruitment of leucocytes. 
In addition to the TZDs, various NSAIDs are PPARγ ligands, and 15dPGJ2 and 13HODE and 15HETE [Table - 1].  The cyclopentenone 15dPGJ2 might seem desirable as a therapeutic agent, for it is an NFkB inhibitor  and it can prevent macrophage activation.  Actually at low micromolar concentrations it is proinflammatory  and larger concentrations must be sustained for beneficial effect! One can assume that an elevated expression of PPARD on renal tubular epithelial cells and on mesangial cells will service to restrict tissue damage, as can be demonstrated with unilateral renal obstruction in rats.  However under normal circumstances these receptors have restricted tissue distribution.  PPARα species that play a major role in fatty acid utilization colocalize with P450 4A enzymes in the proximal tubules and thick limbs. PPARγ are predominantly in the collecting ducts, but present also on mesangial cells. The distribution suggests functions related to water and sodium balance and control of blood pressure that are not yet fully elucidated.  Using the mesangial cells of diabetic mice Zheng et al  used transfection with PPARγ expression construct and application of troglitazone to show induced suppression of TGFβ1 and production of type I collagen and mRNA. This confirms the ability of PPARγ to lessen glomerulosclerosis in nondiabetic and diabetic context.
| PPAR and Immune Reactions|| |
Since NFkB promotes iNOS, one might expect PPARγ or PGJ2 to reduce iNOS activity as was shown in mesangial cells.  Yet in spite of NFkB inhibition some PPAR agonists act via independent mechanisms to promote iNOS expression in mesangial cells.  Generally NO is anti-inflammatory and will downregulate cytokine formation.
There are big differences between murine and human dendritic cells (DCs) and elucidation of some problems is slow. Using human monocyte derived DCs Gosset et al  found that PPARγ activation inhibited secretion of I1-12 which could indicate that they become DC-2 which will impair formation of Th-1 lymphocytes. Now Nencioni et al  report that activation of PPARγ during DC differentiation so alters costimulatory molecules that there is then impaired ability to activate lymphocytes and to prime cytotoxic T cells. So the TZDs might create more profound immunosuppression than anticipated in some persons.
Troglitazone and 15dPGJ2 inhibit production of I1-2 and PHA induced T lymphocyte proliferation in proportion to dosage  and PPARγ agonists can induce apoptosis of human B lineage cells.  Add to these facts the information that PPARγ activators inhibit IFNγ induced expression of chemokines for T cells like IP-10,  and TNFa induction of the selectins  and one has a very good case for suggesting that PPARγ agonists could be important adjunct therapy for conditions like lupus glomerulonephritis. Clearly the TZDs will be advantageous in persons who might be subject to complications of corticosteroid therapy, but they can cause weight gain and fluid retention in proportion to dosage.
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E Nigel Wardle
37 Princess Road, Camden, London NW1 8JS
[Table - 1]