batch_1/PMC2531205.json

{
    "id": "PMC2531205",
    "text": "This is an academic paper. This paper has corpus identifier PMC2531205\nAUTHORS: Tianxin Yang, Sunhapas Soodvilai\n\nABSTRACT:\nThiazolidinediones (TZDs) are peroxisome proliferator-activated receptor subtype γ (PPARγ) activators that are clinically used as an insulin sensitizer for glycemic control in patients with type 2 diabetes. Additionally, TZDs exhibit novel anti-inflammatory, antioxidant, and antiproliferative properties, indicating therapeutic potential for a wide variety of diseases associated with diabetes and other conditions. The clinical applications of TZDs are limited by the common major side effect of fluid retention. A better understanding of the molecular mechanism of TZD-induced fluid retention is essential for the development of novel therapies with improved safety profiles. An important breakthrough in the field is the finding that the renal collecting duct is a major site for increased fluid reabsorption in response to rosiglitazone or pioglitazone. New evidence also indicates that increased vascular permeability in adipose tissues may contribute to edema formation and body weight gain. Future research should therefore be directed at achieving a better understanding of the detailed mechanisms of TZD-induced increases in renal sodium transport and in vascular permeability.\n\nBODY:\n1. INTRODUCTIONThiazolidinediones (TZDs), such as rosiglitazone and pioglitazone,\nare highly effective for the treatment of type 2 diabetes and are widely\nprescribed. Unfortunately, fluid retention has emerged as the most common and\nserious side effect of TZDs and has become the most frequent cause of\ndiscontinuation of therapy. The incidence of TZD-induced fluid retention ranges\nfrom 7% in monotherapy and to as high as 15% when combined with insulin [1–3]. The fluid\nretention is often presented as peripheral edema, which can progress into pulmonary\nedema and congestive heart failure. TZD use leads to a 6-7% increase in\nblood volume in healthy volunteers [4, 5]. This blood\nvolume expansion can dilute the red blood cell concentration, producing a\nreduced hematocrit. In fact, changes in hematocrit have been used as a\nsurrogate marker for TZD-induced plasma volume expansion. The fluid retention\nis often resistant to loop diuretics but is reversed by withdrawing the drug. Many\naspects of TZD-induced fluid retention have been covered by excellent review\narticles [6–12]. This review will emphasize renal sodium retention and vascular\nhyperpermeability as prominent mechanisms of TZD-induced fluid retention. We\nwill also introduce several possible treatment strategies.2. RENAL MECHANISMThe kidney is the key regulator of electrolyte balance and water conservation. Fluid\nretention at the renal level is suggested by evidence that TZD-induced edema is\nassociated with reduced urinary sodium and water excretion. Song et al.\nreported that chronic three-day administration of rosiglitazone to Sprague Dawley\nrats significantly reduced urine volume (by 22%) and sodium excretion (by 44%) [13]. These findings lead us to speculate that\nrenal mechanisms play a major role in TZD-induced fluid retention. TZDs may\ncause renal fluid reabsorption directly by affecting tubular transport, renal\nsodium retention, and vascular hyperpermeability or indirectly by affecting\nrenal hemodynamics or processes. Yang et al. examined the effect of a PPARγ\nagonist, GI262570 (farglitazar), on the glomerular filtration rate, effective\nrenal plasma flow, and renal filtration fraction in chronically\ncatheter-implanted conscious rats [14]. In this\nstudy, glomerular filtration rate was determined by using fluorescein\nisothiocyanate (FITC)-inulin and renal blood\nflow by using para-aminohippurate (PAH). A 10-day infusion of GI262570\ndecreased hematocrit, hemoglobin, and serum albumin (all P < .05), indicating volume expansion, but did not alter\nglomerular filtration rate, effective renal plasma flow, or renal filtration\nfraction. This indicates that PPARγ agonist-induced volume expansion is not\nrelated to changes in renal hemodynamics [14]. This\nobservation is reinforced by a human study in which the six-week administration\nof pioglitazone to healthy volunteers led to sodium retention without a significant\neffect on glomerular filtration rate or renal blood flow [15]. This lack\nof change in renal hemodynamics is, however, not universally reported. The three-day\nadministration of rosiglitazone in Sprague Dawley rates induced a 35% reduction\nin creatinine clearance, an indirect measure of the glomerular filtration rate [13]. It is\nunclear whether or not this discrepancy is related to differences in glomerular\nfiltration rate measurement techniques or other experimental protocols.The lack of solid evidence to support\nthe alteration of renal hemodynamic parameters following treatment with PPARγ\nligands suggests the possibility of a direct influence on tubular transport processes.\nThe regulation of NaCl reabsorption in the kidney can occur at the level of sodium\ntransport proteins lining the renal epithelia. These sodium transporters\ninclude basolateral Na-K-ATPase, and the following apical transporters that\nvary with individual nephron segments: the sodium hydrogenexchanger\nsubtype III (NHE3) and the sodium phosphate cotransporter subtype II (NaPi-2) in the proximal\nconvoluted tubule, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2\nor BSC1) in the thick ascending limb, the thiazide-sensitive Na-Cl cotransporter (NCC or TSC)\nin the distal convoluted tubule, and the amiloride-sensitive sodium channel\n(ENaC) in the collecting duct. The major water channel proteins (aquaporins,\nAQPs) in the kidney include AQP1-4, of which AQP1 and AQP2 function\non the apical membrane, and AQP3 and AQP4 on the basolateral\nmembrane [16]. The study of Song et al. is the first to\nprovide a comprehensive examination of the effects of PPARγ agonists on various\nrenal sodium and water transport proteins [13]. In that study, a three-day rosiglitazone\ntreatment increasedthe whole kidney protein level of the α-1 subunit of Na-K-ATPase, NKCC2,\nNHE3, AQP2, and AQP3 [13]. These findings suggest that increases in\nsodium transport may occur in the proximal convoluted tubule and the thick\nascending limb.The collecting duct reabsorbs approximately 2-3% of the filtered\nsodium load primarily through ENaC, which is comprised of three subunits, α, β,\nand γ. These proteins are vital to day-to-day adjustment of sodium reabsorption\nand are regulated by the hormones aldosterone and insulin [17–19]. A key\nmediator of aldosterone activation of ENaC is serum and glucocorticoid\nregulated kinase 1 (SGK1) [20, 21]. Activated SGK1 prevents ENaC degradation by inactivating the ubiquitin\nligase Nedd4-2 [22]. Nedd4-2\ninteracts with the PY motif of ENaC leading to endocytosis and degradation of\nthe channel [22]. Prior to\nthe conditional knockout (KO) studies, three major lines of evidence indicated\nthat the activation of sodium transport processes in the distal nephron may\nunderlie TZD-induced fluid retention. First, within the kidney, PPARγ is highly expressed in the renal medullary\ncollecting duct, with lower expression levels in glomeruli, proximal tubules,\nand microvasculature. This was demonstrated by both RT-PCR and microdissection as well as by in situ hybridization techniques [23–25]. Second, in\na cultured human cortical collecting duct (CCD) cell line, PPARγ agonists\nincreased levels of cell surface α-ENaC. This is paralleled by an increase in SGK1 mRNA, which is abolished by pretreatment with\na specific PPARγ antagonist, leading to increased levels of cell surface α-ENaC.\nElectrophoretic mobility shift assays further suggest that these effects are\ncaused by the binding of PPARγ to a specific response element in the SGK1 promoter [20]. Third, in vivo evidence shows that GI262570 stimulates\nsodium and water reabsorption from the distal nephron in Sprague Dawley rats [26]. This\nevidence comes from increases in plasma sodium and chloride concentrations with\nconcomitant decreases in plasma potassium concentration. Reciprocal changes in\nplasma NaCl and potassium levels are typically seen as a consequence of renal\nmineralocorticoid activation promoting NaCl reabsorption and potassium\nsecretion in the distal nephron [26]. Additionally,\nmRNA levels for a group of genes involved in distal nephron sodium and water\nabsorption in the kidney medulla are changed with GI262570 treatment [26].The involvement of the distal nephron in TZD-induced fluid retention has been assessed in two independent\nstudies using mice with a collecting duct-specific deletion of PPARγ (CD PPARγ KO) \n[27, 28]. In both studies, the expression of Cre recombinase was driven by an\nAQP2 promoter highly specific to the collecting duct. In these two studies, the\nexperimental approaches for assessment of fluid retention were quite different:\na combination of hematocrit, plasma aldosterone levels, and Evans blue (EB) dye-based\nmeasurement of plasma volume in one study (see Figure 1) [28] and\ndetermination of total water content in the other [27]. Remarkably,\nboth studies reported a similar phenotype in that the conditional PPARγ\nknockout mice proved to be resistant to the rosiglitazone- or\npioglitazone-induced body weight gain and plasma volume expansion found in mice\nexpressing PPARγ in the collecting duct. As shown in Figure 1, a nine-day\nrosiglitazone treatment induced a gradual and significant increase in body\nweight in floxed mice when compared to untreated floxed controls (2.74 ± 0.25 versus 1.05 ± 0.16 gram, on day 9, P < .05). In contrast,\nbody weight gains between rosiglitazone-treated and untreated CD PPARγ KO mice\nwere not significantly different (0.90 ± 0.25 versus 0.81 ± 0.19\ngram, on day 9, P > .05). Rosiglitazone treatment in the control mice\ninduced plasma volume expansion, which was reflected by a significantly\ndecreased hematocrit and plasma aldosterone levels as well as by a 32.2%\nincrease in plasma volume as assessed by the EB dye technique. In contrast,\nrosiglitazone-treated CD PPARγ KO mice exhibited nonsignificant trends toward\nchange in these parameters (see Figure 2). These two studies also provided\nevidence that exposure of primary collecting duct cells to PPARγ ligands leads\nto increased sodium transport as assessed by measurements of 22Na+ flux and transepithelial resistance.Guan et al. examined the effects of pioglitazone on the expression of α-, ß-, and γ-ENaC\nsubunits in cultured inner medullary collecting duct (IMCD) cells [27]. Notably, within one hour following treatment\nof IMCDs with pioglitazone (1 μM), γ-ENaC mRNA expression\nincreased roughly 10 folds\nbefore gradually diminishing. This stimulatory effect appeared to be specific\nfor γ-ENaC mRNA, because α-ENaC and ß-ENaC mRNA levels did not show any change\nin response to treatment with pioglitazone. Interestingly, PPAR response elements (PPREs) are identified in intron 1 but not in the\n5′ flanking region of the γ-ENaC gene. Chromatin immunoprecipitation (ChIP) of\ngenomic DNAisolated from cultured\nmouse IMCDs revealed a physical interaction between PPARγ and γ-ENaC genomic DNA. Somewhat unexpectedly, the PPARγ binding site\nwas shown to be located outside intron 1 of the γ-ENaC gene. Overall, these\ndata support γ-ENaC as a direct target gene of PPARγ in the collecting duct\ncells, although the exact mechanism remains to be elucidated.However, the role of ENaC as a direct target of PPARγ has not always been demonstrable. Nofziger et al.\nreported that, in collecting duct cell lines, PPARγ agonists failed to enhance\nbasal or insulin-stimulated sodium transport as assessed by measurement of\nshort-circuit current (Isc) [29]. This study\nalso did not find that PPARγ-induced changes in the amount of SGK1 transcript or protein expression. Additionally,\nthere is no solid evidence for major changes in renal expression of any of the\nENaC subunits in response to PPARγ ligands in vivo [13, 26, 30]. More recently, Vallon et al. reported that collecting duct-specific gene\ninactivation of α-ENaC in the mouse does not attenuate the rosiglitazone-induced\nbody weight gain [31]. In this\nstudy, the Hoxb-7 promoter was used to inactivate α-ENaC in the collecting duct,\nwhile leaving ENaC expression in the cortical connecting tubule (CNT) intact [32]. As\nexpected, in the floxed control mice, rosiglitazone treatment (320 mg/kg diet) rapidly\nincreased body weight (ΔBW day 11: 4.5 ± 0.8% versus 1.1 ± 0.6%, P < .05) and\nlowered hematocrit (44 ± 1.0% versus 47 ± 1%, P < .0005), while rosiglitazone treatment increased body weight (ΔBW: 7.3 ± 0.9% versus 0.9 ± 0.7%, P < .0005) and lowered hematocrit (42 ± 2% versus 47 ±\n1%, P < .05) in α-ENaC collecting\nduct knockout mice. These data may argue against collecting duct ENaC playing a\nsignificant role in mediating the adverse effect of rosiglitazone. However,\ninvolvement of ENaC activity in the CNT cannot be ruled out. To resolve this issue, AQP2-Cre mice could be used to\ninactivate ENaC in the entire collecting duct system.The negative results discussed above\nprompt consideration of alternative mechanisms for explaining PPARγ-mediated\nincreases in distal tubular fluid reabsorption. There is a significant amiloride-insensitive\ncomponent in the rosiglitazone-induced increases in sodium transport [28]. The\npossibility exists that increased reabsorption may occur by way of a\nparacellular route. For example, PPARγ may regulate the tight junction leading\nto altered permeability to sodium or other electrolytes. In an in vitromodel of differentiating normal human urothelial (NHU) cells, PPARγ activation in conjunction with epidermal growth factor receptor (EGFR) blockade led to the de novo expression\nof claudin 3 mRNA and protein and downregulation of claudin 2 transcription [33]. These\nresults suggest a role for PPARγ and EGFR signaling\npathways in regulating the tight junction formation in NHU cells. There is an\nintriguing possibility that a similar mechanism may operate in renal epithelial\ncells. Another possible mechanism is that PPARγ may regulate transport of ions other than sodium. Further studies\nare clearly needed to explore not only ENaC-dependent, but also\nENaC-independent mechanisms, for TZD-activated fluid reabsorption in the distal\nnephron.3. VASCULAR MECHANISMPPARγ is expressed in the vascular system [34], including endothelial\ncells [35, 36], vascular\nsmooth muscle cells (VSMC) [37] as well as monocyte/macrophages\n[38, 39]. Several\nlines of evidence suggest that PPARγ regulates various aspects of vascular\nfunction, including capillary permeability. Increased capillary permeability\nleads to extravasation of fluid and is thought to contribute to edema in\npatients treated with TZDs. Donnelly et al. were the first to examine the\ndirect effect of rosiglitazone on endothelial barrier function using an in vitro system of pulmonary artery\nendothelial cell monolayers. Transendothelial albumin flux was measured using EB\ndye-labeled albumin. They found that exposure to high concentrations of rosiglitazone\nfor four hours increased transendothelial albumin flux dose-dependently, with a\nnoticeable effect at 10 μM and a maximal effect at 100 μM. This\nhyperpermeability response to high concentrations of rosiglitazone was fully\nreversible by washing rosiglitazone off the monolayer. After incubation for 24\nto 48 hours, the effect of rosiglitazone began to subside. High concentrations\nof rosiglitazone (0.1–1 mM) are also\nneeded to induce a vasodilator effect in isolated arteries [40]. Future\nstudies, ideally employing gene knockout mice, may determine the extent of\nPPARγ mediation of the vascular response to high concentrations of TZDs. The\nmechanism of TZD-induced capillary permeability is not well characterized but\nmay involve a number of factors, notably vascular endothelial growth factor (VEGF),\nnitric oxide, and protein kinase C, each of which is discussed below.VEGF is a potent cytokine that augments vascular permeability in tumors, healing wounds, retinopathies, many\nimportant inflammatory conditions, and certain physiological processes, such as\novulation and corpus luteum formation [41]. VEGF is estimated to be 50 times more potent than histamine in\nenhancing vascular permeability [41]. The gene transfer of naked plasmid DNA encoding the 165-amino acid isoform of VEGF in patents with peripheral artery\ndisease causes peripheral edema [42]. Evidence\nsuggests an involvement of VEGF in TZD-induced edema. The study of Emorto et\nal. was the first to report that plasma levels of VEGF are significantly \nincreased in troglitazone-treated subjects (120.1 ± 135.0 pg/mL)\ncompared with those treated with diet alone (29.2 ± 36.1 pg/mL), sulfonylurea\n(25.8 ± 22.2 pg/mL), or insulin (24.6 ± 19.0 pg/mL). The effect of\ntroglitazone on increased VEGF levels was further supported by plasma VEGF\nlevels in five patients before treatment (20.2 ± 7.0 pg/mL), after three months\nof troglitazone treatment (83.6 ± 65.9 pg/mL), and three months after\ndiscontinuation (28.0 ± 11.6 pg/mL). These authors further demonstrated that\ntroglitazone, as well as rosiglitazone, at the plasma concentrations observed\nin patients, increased VEGF mRNA levels in 3T3-L1 adipocytes. The finding suggests that PPARγ activation may\ndirectly stimulate expression of VEGF that leads to tissue edema. However, it\nis puzzling that several other studies show that PPARγ negatively regulates\nVEGF signaling. In transformed and primary endometrial cells rosiglitazone or 15-deoxy-delta\n12,14-prostaglandin J2 (15d-PGJ2) decreased VEGF protein\nsecretion [43]. In\ntransiently transfected Ishikawa cells, rosiglitazone repressed VEGF gene\npromoter-luciferase activation with an IC [37] approximately 50 nM. By using\ntruncated and mutated VEGF promoter constructs, this study further revealed\nthat the PPARγ-regulated domain is a direct repeat (DR)-1 motif −443 bp\nupstream of the transcriptional start site [43]. Similarly,\nrosiglitazone attenuated VEGF-induced proliferation and migration of human\npulmonary valve endothelial cells (HPVECs) [44].\nRosiglitazone also antagonized VEGF-induced nuclear factor translocation in activated T cells subtype c1 (NFATc1) [44]. Furthermore,\nrosiglitazone markedly decreased VEGF-induced tube formation and cell migration\nin human umbilical vein endothelial cells [45]. Taking these studies together, it seems likely that PPARγ exerts a dual\neffect on VEGF signaling, possibly depending on cell type.Nitric oxide (NO) is a ubiquitous,\nnaturally occurring molecule found in a variety of cell types and organ\nsystems. Endothelial cells are rich in NO, which has been shown to regulate\nmany aspects of vascular function, including vascular permeability. Polikandriotis\net al. report that 15d-PGJ2 and ciglitazone increase cultured\nendothelial cell NO release without increasing the expression of endothelial\nnitric oxide synthase (eNOS) [46]. This study\nprovided further evidence that PPARγ activation leads to eNOS ser1177\nphosphorylation [46]. It seems\nplausible that the stimulation of eNOS-derived NO may contribute to TZD-induced\nedema. St-Pierre et al. examined the effect of rosiglitazone on muscle\nvasopermeability and NO system in the fructose-fed rat model [47]. In this\nstudy, extravasation of EB dye in vivo\nin specific muscle groups was used to assess vascular permeability. Fructose-fed\nrats treated with rosiglitazone had a 30–50% increase in extravasation\nof EB in the the Rectus femoris, soleus, gastrocnemius lateralis, vastus\nlateralis, and tibialis cranialis skeletal muscles [47]. In\nhomogenates of skeletal muscles (vastus lateralis) from fructose-fed rats,\nrosiglitazone resulted in a significant increase in nitric oxide synthase (NOS)\nactivity and eNOS immunoreactive content compared to the control animals [47].\nUnexpectedly, the immunoreactive level of the most abundant muscle NOS\nisoforms, neuronal NOS (nNOS), remained unchanged.Protein kinase C (PKC) plays a major role in determining vascular permeability through\nphosphorylation of the cytoskeleton proteins that form the tight intercellular\njunction [48–51]. In the study of Sotiropoulos et al., rosiglitazone treatment\nselectively activated PKC in fat and retinal tissues in parallel with the\nincreased vascular permeability in these tissues [52]. The activation of PKC is evaluated by\ndetermining the enzyme activity together with tissue levels of diacylglycerol (DAG), a\nstrong PKC activator [52]. These investigators tested the effect\nof PKCβ inhibition and gene knockout but did not determine specific PKC\nisoforms. They found that posttreatment with ruboxistaurin (RBX), a PKCβ inhibitor,\neffectively attenuated the increases in capillary permeability, water content,\nand weight of epididymal fat, as well as the increase in body weight associated\nwith rosiglitazone treatment; this finding was also confirmed by using PKCβ KO mice\n[52].4. POTENTIAL THERAPIES4.1. Inhibition of sodium transport in the collecting ductThe use of diuretics for management of TZD-induced fluid retention has been evaluated\nby several case reports [2, 53] and, \nrecently, by a controlled trial [54]. Most case reports show that the edema\nis refractory to a loop diuretic (furosemide) and that the symptoms resolve\nonly after discontinuation of TZD. The recent controlled trial involved 381\npatients with type 2 diabetes. It examined the effect of three diuretics that\nact with different mechanisms on rosiglitazone-induced body weight gain and\nplasma volume [54]. The diuretics included furosemide,\nwhich inhibits the Na-K-Cl cotransporter in the thick ascending limb of the loop\nof Henle, hydrochlorothiazide (HCTZ), which acts to inhibit the Na-Cl\ncotransporter in the distal convoluted tubule, and spironolactone (SPIRO), which\nis an ENaC inhibitor in the collecting duct. The degree of fluid retention in\nthis study was evaluated by measuring changes in the hematocrit as an index of\nchanges in plasma volume, body weight, total body water, and extracellular\nfluid changes determined by noninvasive bioelectrical impedance with an Akern\nsoft tissue analyzer. SPIRO and HCTZ both effectively reduced fluid retention\nand body weight while furosemide had only a limited effect. The effectiveness\nof SPIRO may be attributable to the ability of this diuretic to interfere with\nthe sodium retaining action of PPARγ in the collecting duct. It is unclear\nwhether the same mechanism can explain the action of HCTZ. Thiazide diuretics act\nprimarily in the proximal part of the distal convoluted tubules where they\ninhibit Na+/Cl− cotransport [55, 56], but they are also reported to inhibit\nsalt and water reabsorption in the medullary collecting duct [57]. The reason for the lack of diuretic response\nof TZD-treated diabetics to furosemide is not entirely clear, but one possible\nexplanation might be the lack of distal effect of this loop diuretic. Another possibility\nis that TZD-induced fluid retention may be associated with impaired transport machinery\nin the thick ascending limb. Possibly secondary to the volume expansion, the\nplasma level of atrial natriuretic factor (ANF)\nis elevated in TZD-treated diabetics [54]. ANF inhibits NaCl reabsorption in the loop of Henle as well as in other sites of\nnephron through the activation of guanylyl cyclase\nreceptors that release cyclic GMP [58]. It also\nremains possible that PPARγ may negatively affect NaCl transport in the loop of\nHenle.The experimental evidence favoring\nENaC as a potential target of PPARγ in the distal nephron seems to provide a\nrationale for the use of amiloride as a specific ENaC inhibitor for treatment\nof TZD-induced fluid retention. Unfortunately, amiloride was not included in\nthis clinical trial [54]. In the mouse, pretreatment with\namiloride effectively prevents body weight gain and fluid retention produced by\npioglitazone. However, in the rat model, posttreatment with amiloride\nunexpectedly exacerbates the fluid retention induced by farglitazar. It is\nunclear whether this discrepancy between the studies is due to species\ndifferences, PPARγ ligand activity, or the different timing of amiloride\ntreatment.4.2. Combination of a PPARγ and a PPARα agonistBoden et al. examined the effect of the\ncombined use of rosiglitazone and fenofibrate in patients with type 2 diabetes [59]. Compared with rosiglitazone alone,\nrosiglitazone/fenofibrate proved significantly more effective in lowering\nfasting free fatty acid levels and tended to be more effective in achieving plasma\nglucose control. Interestingly, rosiglitazone/fenofibrate completely prevented\nthe increase in body weight and body water content associated with\nrosiglitazone. This study is the first to show that the combined use of a PPARγ\nand a PPARα agonist can prevent rosiglitazone-induced fluid retention. The\ninvestigators did not propose a mechanism to explain this phenomenon. The two\nPPAR isoforms occur in different locations along the nephron. PPARα mRNA is found predominately in the cortex and is\nspecifically localized in the proximal convoluted tubule (PCT). PPARγ is\nabundant in the renal inner medulla, specifically localized to the inner\nmedullary collecting duct [23, 25]. The\ndifference in nephron localization does not seem to favor the direct interaction\nbetween the two PPAR isoforms. However, it remains possible that low PPARα\nactivity in the collecting duct may antagonize the sodium-retaining action of\nPPARγ. Future studies are needed to investigate whether an interaction occurs\nin the collecting duct or another location.Dual PPARα/γ agonists\nhave been developed by several pharmaceutical companies, and some have\nundergone or are currently undergoing clinical trials [60–62]. Unfortunately,\nmuraglitazar, the first dual PPARα/γ agonist, has been associated with an\nexcessive incidence of major adverse cardiovascular events, including myocardial\ninfarction, stroke and transient ischemic attack, chronic heart failure and\ndeath [62]. This\nfinding raises significant safety concerns about the dual agonists as well as the combination of a PPARγ and a PPARα agonist. In the study of\nBoden et al., rosiglitazone/fenofibrate appeared to be well tolerated [59]. The safety issues may be related to\nthe ratio of PPARγ to PPARα. The ratios are fixed for the dual agonists, but can\nbe varied by changing the proportion of PPARγ and PPARα agonists. It should be\npointed out that Boden's study was limited to a small number of patients and a\nshort period of treatment [59]. The safety issue regarding the\ncombined use of a PPARγ and PPARα agonist needs to be carefully evaluated in\nlarger-scale and longer-term clinical trials as well as animal studies.4.3. Inhibition of protein kinase CThere is functional evidence suggesting\nthe involvement of vascular permeability in TZD-induced body weight gain and\nfluid retention [52]. Therefore, targeting vascular\npermeability may provide a potential therapeutic strategy for this side effect\nof the TZDs. In an animal study, the use of a PKCβ inhibitor, RBX, to target\nvascular permeability effectively attenuated the increases in TZD-induced body\nweight gain [52]. Is there any safety issue related to\nRBX? In the animal models tested, including Zucker and lean fatty rats, and mice,\nRBX reduced rosiglitazone-induced capillary permeability, but had no\nsignificant effect on the baseline capillary permeability without rosiglitazone\ntreatment. In this short-term animal study, the compound appears to be well\ntolerated. Another positive note is that RBX is being used in clinical trials\nfor diabetic microvascular complications. In these trials, as well as in animal\nstudies, RBX shows promise for treatment of diabetic retinopathy and nephropathy\nwithout noticeable side effects [63, 64].5. CONCLUSIONSThe fluid retention and rapid body weight\ngain induced by TZD treatment are caused by increased fluid reabsorption in the\ndistal nephron as well as increased vascular permeability in adipose tissues (see Figure 3).\nThe molecular mechanisms of the effects of TZDs in renal collecting duct and in\nblood vessels remain unknown. Despite documentation of ENaC as a molecular target\nof TZDs in the collecting duct, increasing evidence indicates ENaC-independent\nmechanisms that may involve changes in paracellular transport. PKCß is shown to\nmediate TZD-induced vascular permeability in adipose tissues. More studies are\nrequired for determination of the signaling pathway responsible for PPARγ-dependent\ntissue-specific activation of PKCß. Currently,\nthere are no effective therapies for the side effects of TZDs except drug\nwithdrawal. A number of potential treatment strategies that target collecting\nduct sodium transport (amiloride) and vascular permeability (PKC inhibitors)\nhave been developed from animal studies and should be evaluated by future clinical\ntrials.\n\nREFERENCES:\n1. FüchtenbuschMStandlESchatzHClinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitusExperimental and Clinical Endocrinology & Diabetes2000108315116310926309\n2. HirschIBKellyJCooperSPulmonary edema associated with troglitazone therapyArchives of Internal Medicine199915915p. 1811\n3. ThomasMLLloydSJPulmonary edema associated with rosiglitazone and troglitazoneThe Annals of Pharmacotherapy200135112312411197573\n4. (Pioglitazone) PIA. Takeda Pharmaceuticals, Inc.\n5. (Rosiglitazone) PIA. GlaxoSmithKline Pharmaceuticals\n6. DuanSZUsherMGMortensenRMPeroxisome proliferator-activated receptor-γ-mediated effects in the vasculatureCirculation Research2008102328329418276926\n7. HollenbergNKConsiderations for management of fluid dynamic issues associated with thiazolidinedionesThe American Journal of Medicine20031158, supplement 111111512893396\n8. KalambokisGNTsatsoulisAATsianosEVThe edematogenic properties of insulinAmerican Journal of Kidney Diseases200444457559015384008\n9. NestoRWBellDBonowROThiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes AssociationCirculation2003108232941294814662691\n10. NiemeyerNVJanneyLMThiazolidinedione-induced edemaPharmacotherapy200222792492912126225\n11. RubenstrunkAHanfRHumDWFruchartJ-CStaelsBSafety issues and prospects for future generations of PPAR modulatorsBiochimica et Biophysica Acta2007177181065108117428730\n12. TangWHWMarooAPPARγ agonists: safety issues in heart failureDiabetes, Obesity and Metabolism200794447454\n13. SongJKnepperMAHuXVerbalisJGEcelbargerCARosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal ratsJournal of Pharmacology and Experimental Therapeutics2004308242643314593089\n14. YangBCliftonLGMcNultyJAChenLBrownKKBaerPGEffects of a PPARγ agonist, GI262570, on renal filtration fraction and nitric oxide level in conscious ratsJournal of Cardiovascular Pharmacology200342343644112960690\n15. ZanchiAChioleroAMaillardMNussbergerJBrunnerH-RBurnierMEffects of the peroxisomal proliferator-activated receptor-γ agonist pioglitazone on renal and hormonal responses to salt in healthy menThe Journal of Clinical Endocrinology & Metabolism20048931140114515001599\n16. KnepperMAWadeJBTerrisJRenal aquaporinsKidney International1996496171217178743483\n17. LoffingJLoffing-CueniDMacherALocalization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortexAmerican Journal of Physiology20002784F530F53910751213\n18. LoffingJPietriLAreggerFDifferential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na dietsAmerican Journal of Physiology20002792F252F25810919843\n19. MasilamaniSKimG-HMitchellCWadeJBKnepperMAAldosterone-mediated regulation of ENaC α, β, and γ subunit proteins in rat kidneyThe Journal of Clinical Investigation19991047R19R2310510339\n20. HongGLockhartADavisBPPARγ activation enhances cell surface ENaCα via up-regulation of SGK1 in human collecting duct cellsThe FASEB Journal20031731966196812923071\n21. SchaferJAAbnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting ductAmerican Journal of Physiology20022832F221F23512110505\n22. StaubOVerreyFImpact of Nedd4 proteins and serum and glucocorticoid-induced kinases on epithelial Na+ transport in the distal nephronJournal of the American Society of Nephrology200516113167317416192418\n23. GuanYZhangYDavisLBreyerMDExpression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humansAmerican Journal of Physiology19972736F1013F10229435691\n24. GuanYZhangYSchneiderADavisLBreyerRMBreyerMDPeroxisome proliferator-activated receptor-γ activity is associated with renal microvasculatureAmerican Journal of Physiology20012816F1036F104611704554\n25. YangTMicheleDEParkJExpression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidneyAmerican Journal of Physiology19992776F966F97310600944\n26. ChenLYangBMcNultyJAGI262570, a peroxisome proliferator-activated receptor γ agonist, changes electrolytes and water reabsorption from the distal nephron in ratsJournal of Pharmacology and Experimental Therapeutics2005312271872515475592\n27. GuanYHaoCChaDRThiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorptionNature Medicine2005118861866\n28. ZhangHZhangAKohanDENelsonRDGonzalezFJYangTCollecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retentionProceedings of the National Academy of Sciences of the United States of America2005102269406941115956187\n29. NofzigerCChenLShaneMASmithCDBrownKKBlazer-YostBLPPARγ agonists do not directly enhance basal or insulin-stimulated Na+ transport via the epithelial Na+ channelPflügers Archiv: European Journal of Physiology2005451344545316170524\n30. MittraSSangleGTandonRIncrease in weight induced by muraglitazar, a dual PPARα/γ agonist, in db/db mice: adipogenesis/or oedema?British Journal of Pharmacology2007150448048717211457\n31. VallonVHummlerERiegTCollecting duct-specific inactivation of αENaC in the mouse kidney does not attenuate rosiglitazone-induced weight gainThe FASEB Journal, Meeting Abstract200822, 947.14\n32. RuberaILoffingJPalmerLGCollecting duct-specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balanceThe Journal of Clinical Investigation2003112455456512925696\n33. VarleyCLGarthwaiteMAECrossWHinleyJTrejdosiewiczLKSouthgateJPPARγ-regulated tight junction development during human urothelial cytodifferentiationJournal of Cellular Physiology2006208240741716688762\n34. Bishop-BaileyDPeroxisome proliferator-activated receptors in the cardiovascular systemBritish Journal of Pharmacology2000129582383410696077\n35. InoueIShinoKNojiSAwataTKatayamaSExpression of peroxisome proliferator-activated receptor α (PPARα) in primary cultures of human vascular endothelial cellsBiochemical and Biophysical Research Communications199824623703749610365\n36. SatohHTsukamotoKHashimotoYThiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARγ on vascular endothelial functionBiochemical and Biophysical Research Communications199925437577639920814\n37. StaelsBKoenigWHabibAActivation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activatorsNature199839366877907939655393\n38. ChinettiGGriglioSAntonucciMActivation of proliferator-activated receptors α and γ induces apoptosis of human monocyte-derived macrophagesJournal of Biological Chemistry19982734025573255809748221\n39. RicoteMLiACWillsonTMKellyCJGlassCKThe peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activationNature1998391666279829422508\n40. RyanMJDidionSPMathurSFaraciFMSigmundCDPPARγ agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic miceHypertension200443366166614744930\n41. DvorakHFNagyJAFengDBrownLFDvorakAMVascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesisCurrent Topics in Microbiology and Immunology1999237971329893348\n42. BaumgartnerIRauhGPieczekALower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factorAnnals of Internal Medicine20001321188088410836914\n43. PeetersLLHVigneJ-LTeeMKZhaoDWaiteLLTaylorRNPPARγ represses VEGF expression in human endometrial cells: implications for uterine angiogenesisAngiogenesis200684373379\n44. SanderTLNollLAKlinknerDBRosiglitazone antagonizes vascular endothelial growth factor signaling and nuclear factor of activated T cells activation in cardiac valve endotheliumEndothelium200613318119016840174\n45. SheuWH-HOuH-CChouF-PLinT-MYangC-HRosiglitazone inhibits endothelial proliferation and angiogenesisLife Sciences200678131520152816297938\n46. PolikandriotisJAMazzellaLJRupnowHLHartCMPeroxisome proliferator-activated receptor γ ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor γ-dependent mechanismsArteriosclerosis, Thrombosis, and Vascular Biology200525918101816\n47. St-PierrePBouffardLMaheuxPRosiglitazone increases extravasation of macromolecules and endothelial nitric oxide synthase in skeletal muscles of the fructose-fed rat modelBiochemical Pharmacology200467101997200415130775\n48. ClarkeHMaranoCWSolerAPMullinJMModification of tight junction function by protein kinase C isoformsAdvanced Drug Delivery Reviews200041328330110854687\n49. ClarkeHSolerAPMullinJMProtein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheetsJournal of Cell Science2000113183187319610954417\n50. StasekJEJrGarciaJGNThe role of protein kinase C in α-thrombin-mediated endothelial cell activationSeminars in Thrombosis and Hemostasis19921811171251574713\n51. StasekJEJrPattersonCEGarciaJGNProtein kinase C phosphorylates caldesmon77 and vimentin and enhances albumin permeability across cultured bovine pulmonary artery endothelial cell monolayersJournal of Cellular Physiology1992153162751522136\n52. SotiropoulosKBClermontAYasudaYAdipose-specific effect of rosiglitazone on vascular permeability and protein kinase C activation: novel mechanism for PPARγ agonist's effects on edema and weight gainThe FASEB Journal20062081203120516672634\n53. WangFAleksunesLMReaganLAVergaraCMManagement of rosiglitazone-induced edema: two case reports and a review of the literatureDiabetes Technology & Therapeutics20024450551412396745\n54. KarallieddeJBuckinghamRStarkieMLorandDStewartMVibertiGEffect of various diuretic treatments on rosiglitazone-induced fluid retentionJournal of the American Society of Nephrology200617123482349017093067\n55. EllisonDHVelazquezHWrightFSThiazide-sensitive sodium chloride cotransport in early distal tubuleAmerican Journal of Physiology19872533F546F5543631283\n56. GesekFAFriedmanPASodium entry mechanisms in distal convoluted tubule cellsAmerican Journal of Physiology19952681F89F987840252\n57. WilsonDRHonrathUSonnenbergHThiazide diuretic effect on medullary collecting duct function in the ratKidney International19832357117166876566\n58. BaillyCTransducing pathways involved in the control of NaCl reabsorption in the thick ascending limb of Henle's loopKidney International. Supplement199865S29S359551429\n59. BodenGHomkoCMozzoliMZhangMKresgeKCheungPCombined use of rosiglitazone and fenofibrate in patients with type 2 diabetes: prevention of fluid retentionDiabetes200756124825517192489\n60. BodenGZhangMRecent findings concerning thiazolidinediones in the treatment of diabetesExpert Opinion on Investigational Drugs200615324325016503761\n61. EtgenGJOldhamBAJohnsonWTA tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-α/γ agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical modelsDiabetes20025141083108711916929\n62. NissenSEWolskiKTopolEJEffect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitusJournal of the American Medical Association2005294202581258616239637\n63. AndersonPWMcGillJBTuttleKRProtein kinase C β inhibition: the promise for treatment of diabetic nephropathyCurrent Opinion in Nephrology and Hypertension200716539740217693752\n64. ClarkeMDodsonPMPKC inhibition and diabetic microvascular complicationsBest Practice & Research in Clinical Endocrinology & Metabolism2007214573586"
}