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• W2088806766 abstract "Doxorubicin (DOX) is an anthracycline antibiotic utilized in antitumor therapy; however, its clinical use is frequently impeded by renal toxic effects. As peroxisome proliferator-activated receptor-α (PPAR-α) has renoprotective effects in drug-related kidney injuries, we tested its ability to inhibit DOX-induced renal injury. Although both male PPAR-α knockout mice and their wild-type littermates (pure 129/SvJ background) had significant proteinuria 4 weeks after DOX treatment, those with deletion of PPAR-α had more severe proteinuria. This was associated with more serious podocyte foot process effacement compared with wild-type mice. In contrast, the PPAR-α agonist fenofibrate effectively reduced proteinuria and attenuated DOX-induced podocyte foot process effacement. Consistently, glomerular nephrin expression was significantly lower in the knockout compared with wild-type mice following DOX treatment. Fenofibrate therapy significantly blunted the reduction in glomerular nephrin levels in DOX-treated wild-type mice. In cultured podocytes, DOX induced apoptosis, increased cleaved caspase-3 levels, and decreased Bcl-2 expression, all attenuated by pretreatment with fenofibrate. Thus, PPAR-α deficiency exacerbates DOX-related renal injury, in part, due to increased podocyte apoptosis. Doxorubicin (DOX) is an anthracycline antibiotic utilized in antitumor therapy; however, its clinical use is frequently impeded by renal toxic effects. As peroxisome proliferator-activated receptor-α (PPAR-α) has renoprotective effects in drug-related kidney injuries, we tested its ability to inhibit DOX-induced renal injury. Although both male PPAR-α knockout mice and their wild-type littermates (pure 129/SvJ background) had significant proteinuria 4 weeks after DOX treatment, those with deletion of PPAR-α had more severe proteinuria. This was associated with more serious podocyte foot process effacement compared with wild-type mice. In contrast, the PPAR-α agonist fenofibrate effectively reduced proteinuria and attenuated DOX-induced podocyte foot process effacement. Consistently, glomerular nephrin expression was significantly lower in the knockout compared with wild-type mice following DOX treatment. Fenofibrate therapy significantly blunted the reduction in glomerular nephrin levels in DOX-treated wild-type mice. In cultured podocytes, DOX induced apoptosis, increased cleaved caspase-3 levels, and decreased Bcl-2 expression, all attenuated by pretreatment with fenofibrate. Thus, PPAR-α deficiency exacerbates DOX-related renal injury, in part, due to increased podocyte apoptosis. Doxorubicin (DOX) is an anthracycline antibiotic used widely in antitumor therapy; however, its clinical use can have a cytotoxic effect on several organs, especially the kidney. The toxic effects of doxorubicin on the renal structure are podocyte foot process effacement and increased glomerular permeability, leading to proteinuria.1.Cheng H. Wang S. Jo Y.I. et al.Overexpression of cyclooxygenase-2 predisposes to podocyte injury.J Am Soc Nephrol. 2007; 18: 551-559Crossref PubMed Scopus (67) Google Scholar, 2.Koshikawa M. Mukoyama M. Mori K. et al.Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome.J Am Soc Nephrol. 2005; 16: 2690-2701Crossref PubMed Scopus (152) Google Scholar, 3.Guo J. Ananthakrishnan R. Qu W. et al.RAGE mediates podocyte injury in adriamycin-induced glomerulosclerosis.J Am Soc Nephrol. 2008; 19: 961-972Crossref PubMed Scopus (83) Google Scholar The mechanisms involved in DOX-associated nephropathy remain incompletely understood. Among many possible pathogenic factors, oxygen free radicals have been thought to have a critical role.4.Vogtlander N.P. Tamboer W.P. Bakker M.A. et al.Reactive oxygen species deglycosilate glomerular alpha-dystroglycan.Kidney Int. 2006; 69: 1526-1534Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5.Pippin J.W. Brinkkoetter P.T. Cormack-Aboud F.C. et al.Inducible rodent models of acquired podocyte diseases.Am J Physiol Renal Physiol. 2009; 269: F213-229Google Scholar Because of this incomplete understanding of underlying mechanisms, the current therapies of DOX-associated nephropathy remain suboptimal, and novel treatments are urgently needed. Recently, a subfamily of the nuclear receptor transcription factors, peroxisome proliferator-activated receptors (PPARs), including PPAR-α, PPAR-β/δ, and PPAR-γ, has been increasingly recognized as key players in the pathogenesis of metabolic syndrome and its renal complications.6.Guan Y. Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.J Am Soc Nephrol. 2004; 15: 2801-2815Crossref PubMed Scopus (157) Google Scholar PPAR-α, as the first identified PPAR isoform, is a target for various long-chain fatty acids and is predominantly expressed in tissues exhibiting high catabolic rates of fatty acids, such as adipose tissue, liver, heart, muscle, and renal cortex.7.Auboeuf D. Rieusset J. Fajas L. et al.Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients.Diabetes. 1997; 46: 1319-1327Crossref PubMed Scopus (637) Google Scholar The actions of PPAR-α are mainly through a ligand-dependent transactivation mechanism, by which PPAR-α heterodimerizes with retinoid X receptor-α and regulates the transcriptional activity of its target genes by binding to the PPAR response element (PPRE) located in the promoter regions of PPAR-α target genes.8.Guan Y. Breyer M.D. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease.Kidney Int. 2001; 60: 14-30Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar PPAR-α is highly abundant in the proximal tubules and medullary thick ascending limbs, with lower levels in the glomeruli.9.Guan Y. Zhang Y. Davis L. et al.Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans.Am J Physiol. 1997; 273: F1013-1022PubMed Google Scholar In general, PPAR-α controls a set of genes essential for fatty acid β-oxidation and has an important role in the metabolic control of renal energy homeostasis.10.Portilla D. Energy metabolism and cytotoxicity.Semin Nephrol. 2003; 23: 432-438Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Besides its role in regulating lipid metabolic role, PPAR-α also shows anti-inflammatory and antifibrotic effects by ligand-dependent transrepressing actions on nuclear factor-κB and activator protein-1 pathways.11.Duval C. Chinetti G. Trottein F. et al.The role of PPARs in atherosclerosis.Trends Mol Med. 2002; 8: 422-430Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 12.Park C.W. Kim H.W. Ko S.H. et al.Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha.Diabetes. 2006; 55: 885-893Crossref PubMed Scopus (120) Google Scholar, 13.Park C.W. Zhang Y. Zhang X. et al.PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice.Kidney Int. 2006; 69: 1511-1517Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 14.Ruan X. Zheng F. Guan Y. PPARs and the kidney in metabolic syndrome.Am J Physiol Renal Physiol. 2008; 294: F1032-F1047Crossref PubMed Scopus (84) Google Scholar The PPAR-α agonist fenofibrate significantly attenuated but PPAR-α gene deficiency markedly worsened albuminuria and glomerular fibrosis in type 2 diabetic db/db mice.12.Park C.W. Kim H.W. Ko S.H. et al.Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha.Diabetes. 2006; 55: 885-893Crossref PubMed Scopus (120) Google Scholar, 13.Park C.W. Zhang Y. Zhang X. et al.PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice.Kidney Int. 2006; 69: 1511-1517Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Recently, activation of PPAR-α by fibrate treatment was also shown to be effective in ameliorating cisplatin-induced renal tubular injury15.Nagothu K.K. Bhatt R. Kaushal G.P. et al.Fibrate prevents cisplatin-induced proximal tubule cell death.Kidney Int. 2005; 68: 2680-2693Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar and DOX-induced apoptosis in renal tubular cells.16.Lin H. Hou C.C. Cheng C.F. et al.Peroxisomal proliferator-activated receptor-alpha protects renal tubular cells from doxorubicin-induced apoptosis.Mol Pharmacol. 2007; 72: 1238-1245Crossref PubMed Scopus (37) Google Scholar Although PPAR-α exerts a renoprotective effect in many renal disorders, whether PPAR-α is involved in the pathogenesis of DOX-associated podocyte injury is unclear. Thus, we aimed to investigate the role of PPAR-α in DOX-induced renal injury in vivo and in vitro and examine whether PPAR-α activation could represent a preventive maneuver for DOX-associated nephrotoxicity. Following DOX treatment, both WT and PPAR-α−/− mice on a 129/SvJ background showed significant albuminuria, with more severe proteinuria and hypoalbuminemia in PPAR-α−/− mice than in WT mice (Figure 1). Consistently, DOX-treated PPAR-α−/− mice exhibited higher plasma cholesterol and triglyceride levels than did WT mice (Table 1). Electron microscopy revealed podocyte foot process effacement in both groups (Figure 2A). In each photograph, the mean of the foot process width was calculated as described in the Materials and Methods. As shown in Figure 2B, DOX treatment resulted in more severe podocyte foot process effacement in PPAR-α−/− mice than in WT mice on a 129/SvJ background (foot process width 2446±37.04 vs 854.4±30.94 nm, P<0.01).Table 1Metabolic and physiological parameters in DOX-treated WT and PPAR-α knockout miceWTWT+DOXPPAR-α−/−PPAR-α−/−+DOXBody weight (g)26.76±0.5525.22±0.5125.12±0.4120.74±0.83**P<0.01 vs PPAR-α−/−;,P<0.01 vs WT+DOX.Liver/body weight (%)3.99±0.104.32±0.114.21±0.115.50±0.16**P<0.01 vs PPAR-α−/−;,P<0.01 vs WT+DOX.Kidney/body weight (%)0.69±0.010.65±0.020.65±0.030.60±0.02Fat/body weight (%)1.61±0.191.50±0.271.83±0.140.69±0.04**P<0.01 vs PPAR-α−/−;,P<0.01 vs WT+DOX.Plasma cholesterol (mg/dl)114.8±11.18198.4±36.01136.6±15.27390.2±23.89**P<0.01 vs PPAR-α−/−;,P<0.01 vs WT+DOX.Plasma triglyceride (mg/dl)98.72±10.98173.3±28.04112.9±12.24296.8±30.57**P<0.01 vs PPAR-α−/−;,P<0.01 vs WT+DOX.Abbreviations: DOX, doxorubicin; PPAR-α, peroxisome proliferator-activated receptor-α; WT, wild type.P<0.01 vs WT;## P<0.01 vs PPAR-α−/−;++ P<0.01 vs WT+DOX. Open table in a new tab Figure 2Doxorubicin (DOX)-induced podocyte foot process effacement in peroxisome proliferator-activated receptor-α (PPAR-α) wild-type (WT) and knockout mice. (a) Representative electron microscopy images of podocyte foot processes: (A) WT; (B) WT with DOX (WT+DOX); (C) PPAR-α knockout (PPAR-α−/−); (D) PPAR-α knockout with DOX (PPAR-α−/−+DOX). (b) Quantification of foot process effacement. Data are means±s.e.m. **P<0.01 vs WT; ##P<0.01 vs PPAR-α−/−; ++P<0.01 vs WT+DOX, N=5.View Large Image Figure ViewerDownload (PPT) Abbreviations: DOX, doxorubicin; PPAR-α, peroxisome proliferator-activated receptor-α; WT, wild type. P<0.01 vs WT; The expression of nephrin in the glomeruli and the kidneys was measured by immunohistochemistry and real-time PCR (RT-PCR), respectively. As expected, strong glomerular nephrin immunoreactivity was observed in WT mice (Figure 3A). Although the expression of nephrin was markedly decreased in the glomeruli of both DOX-treated WT and PPAR-α−/− mice, nephrin immunoreactivity was significantly lower in PPAR-α−/− than in WT mice after DOX treatment (Figure 3A and B). RT-PCR analysis of renal nephrin expression further showed that the levels of nephrin mRNA expression was significantly lower in PPAR-α−/− than in WT mice after DOX treatment (Figure 3C). Treatment with a PPAR-α agonist fenofibrate for 1 month significantly reduced the level of DOX-induced proteinuria, although the levels remained higher than that in controls (Figure 4a). DOX-treated mice exhibited decreased plasma albumin levels, with no significant difference in levels between DOX and fenofibrate-treated mice (Figure 4b). Plasma cholesterol and triglyceride levels showed a slight but not significant increase in the DOX group (Table 2). Electron microscopy revealed DOX-treated mice with more severe podocyte foot process effacement than control mice, and fenofibrate treatment significantly improved podocyte foot process effacement induced by DOX (Figure 5).Table 2Metabolic and physiological parameters in DOX-treated mice with or without fenofibrate treatmentConDOXFib+DOXBody weight (g)25.95±1.0524.35±0.3323.78±0.49Liver/body weight (%)3.93±0.244.21±0.375.37±0.45*P<0.05 vs Con;,#P<0.05 vs DOX.Kidney/body weight (%)0.69±0.030.67±0.030.66±0.02Fat/body weight (%)1.41±0.101.24±0.120.86±0.11*P<0.05 vs Con;,#P<0.05 vs DOX.Plasma cholesterol (mg/dl)96.98±7.56138.2±16.7386.99±11.36Plasma triglyceride (mg/dl)83.94±12.49116.3±21.7480.42±12.95Abbreviations: Con, control; DOX, doxorubicin; Fib, fenofibrate.* P<0.05 vs Con;# P<0.05 vs DOX. Open table in a new tab Figure 5Fenofibrate treatment ameliorated podocyte foot process effacement in doxorubicin (DOX)-treated mice. (a) Representative electron microscope images of podocyte foot processes: (A) control (Con); (B) DOX (DOX); and (C) fenofibrate+DOX (Fib+DOX). (b) Quantification of foot process effacement. Data are means±s.e.m. **P<0.01 vs Con; ##P<0.01 vs DOX, N=5.View Large Image Figure ViewerDownload (PPT) Abbreviations: Con, control; DOX, doxorubicin; Fib, fenofibrate. We further verified the renoprotective role of PPAR-α in DOX-induced renal injury in mice of a pure BALB/c background. Consistent with the findings observed in 129/SvJ mice, PPAR-α agonist fenofibrate significantly improved DOX-associated nephropathy in BALB/c mice (Supplementary Figures S1–4 online). Fenofibrate treatment significantly reduced proteinuria levels and attenuated podocyte foot process effacement (Supplementary Figure S1 online). Fenofibrate treatment also lowered blood urea nitrogen levels and reduced urinary KIM-1 (kidney injury molecule-1) excretion (Supplementary Figure S2 online). Glomeruloscelerosis and tubulointerstitial fibrosis were markedly ameliorated after fenofibrate treatment (Supplementary Figure S3 online). Moreover, fenofibrate treatment significantly restored glomerular nephrin expression in DOX-treated BALB/c mice (Supplementary Figure S4 online). Collectively, these results confirm the findings in 129/SvJ mice and support our conclusion that PPAR-α agonists represent potential preventive agents for DOX-induced nephropathy. Download .jpg (.05 MB) Help with files Supplementary Figure 1 Download .jpg (.03 MB) Help with files Supplementary Figure 2 Download .jpg (.08 MB) Help with files Supplementary Figure 3 Download .jpg (.06 MB) Help with files Supplementary Figure 4 We examined the protective effect of fenofibrate on DOX-induced renal injury in PPAR-α gene knockout mice (Supplementary Figure 5, Supplementary Figure 6, Supplementary Figure 7, Supplementary Figure 8 online). The results showed that fenofibrate had little effect on proteinuria (Supplementary Figure S5A online), plasma albumin levels (Supplementary Figure S5B online), podocyte foot process effacement (Supplementary Figure S5C and D online), blood urea nitrogen and serum creatinine levels (Supplementary Figure S6A and B online), urinary KIM-1 excretion (Supplementary Figure S6C online), glomerular histology (Supplementary Figure S7online), and nephrin expression (Supplementary Figure S8online) in PPAR-α knockout mice. Download .jpg (.04 MB) Help with files Supplementary Figure 5 Download .jpg (.03 MB) Help with files Supplementary Figure 6 Download .jpg (.06 MB) Help with files Supplementary Figure 7 Download .jpg (.04 MB) Help with files Supplementary Figure 8 The immunoreactivity of nephrin was markedly decreased in glomeruli from DOX-treated mice on a pure 129/SvJ background, which was significantly improved by fenofibrate treatment by immunohistochemistry (Figure 6A and B). RT-PCR analysis further revealed that fenofibrate treatment increased nephrin mRNA expression in DOX-treated mice (Figure 6D). Immunofluorescence study demonstrated that nephrin distribution was changed from a fine, linear-like to discontinuous, coarse granular pattern in control mouse after DOX treatment, which was attenuated by treatment with fenofibrate (Figure 6C).These findings further support the results of electron microscopy studies on podocytes shown in Figures 2 and 5. Similarly, fenofibrate treatment also significantly improved the DOX-induced decrease in nephrin expression at both mRNA and protein levels in BALB/c mice (Supplementary Figure S4 online). Although PPAR-α is abundantly expressed in the proximal tubules and medullary thick ascending limbs, as assessed by in situ hybridization9.Guan Y. Zhang Y. Davis L. et al.Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans.Am J Physiol. 1997; 273: F1013-1022PubMed Google Scholar and immunohistochemistry (Supplementary Figure S9A online), low but functional PPAR-α expression was also reported in glomerular cells including mesangial cells and podocytes.6.Guan Y. Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.J Am Soc Nephrol. 2004; 15: 2801-2815Crossref PubMed Scopus (157) Google Scholar, 8.Guan Y. Breyer M.D. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease.Kidney Int. 2001; 60: 14-30Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar Using RT-PCR, we found that PPAR-α was constitutively expressed in freshly isolated mouse glomeruli (Supplementary Figure S9B online). RT-PCR, western blot analysis, and PPRE 3 × luciferase reporter analysis further revealed the presence of PPAR-α in podocytes. Both PPAR-α mRNA and protein were detected in culture podocytes (Figure 7a). PPRE luciferase reporter analysis further demonstrated that fenofibrate treatment significantly increased luciferase activity in podocytes (Figure 7b), which suggests a functional expression of PPAR-α in these cells. To test whether DOX suppression of PPRE-Luc activity is specific to the PPAR-α pathway, we cultured primary glomerular mesengial cells from PPAR-α knockout mice. As shown in Supplementary Figure S10 online, DOX significantly reduced PPRE-luciferase activity as seen in podocytes, and fenofibrate treatment did not increase PPRE activity in PPAR-α-deficient mesengial cells. It implies that DOX-suppressed PPRE-luciferase activity may be shared among signaling cascades downstream PPAR-β and/or PPAR-γ. Download .jpg (.04 MB) Help with files Supplementary Figure 9 Download .jpg (.03 MB) Help with files Supplementary Figure 10 Renal PPAR-α expression and localization was further analyzed using RT-PCR and immunohistochemistry. DOX treatment resulted in a significant reduction in PPAR-α mRNA and protein levels in whole kidneys (Supplementary Figure S9A and C online), with little effect on intrarenal localization of PPAR-α protein (Supplementary Figure S9A online). Consistently, DOX-treated podocytes exhibited reduced PPAR-α mRNA levels (Supplementary Figure S9D online) and endogenous PPAR-α activity (Figure 7b). As expected, PPAR-α expression was not present in PPAR-α gene-deficient mice (Supplementary Figure S9E online), and its level in podocytes was lower than in the glomeruli and the kidneys (Supplementary Figure S9F online). Interestingly, PPAR-α activation by fenofibrate treatment attenuated the inhibitory effect of DOX on PPAR-α transcription activity (Figure 7b). Fenofibrate treatment also increased transcription of PPAR-α target genes CYP4A10 and CYP4A14, although DOX-treated podocytes only slightly decreased the expression of these genes (Figure 7c and d). Fluorescence-activated cell sorting was performed to measure apoptosis. Podocytes were stained with Annexin V–fluorescein isothiocyanate and propidium iodide to distinguish viable, apoptotic, and necrotic cells. As expected, DOX induced significant apoptosis compared with untreated cells and fenofibrate treatment significantly attenuated DOX-induced apoptosis. Fenofibrate alone did not affect apoptosis in normal podocytes (Figure 8a). These findings were further supported by a significant reduction in DOX-induced glomerular cell apoptosis after fenofibrate treatment (Supplementary Figure S11 online). Download .jpg (.05 MB) Help with files Supplementary Figure 11 In line with these apoptotic changes, Bcl-2 (B-cell lymphoma 2) mRNA expression was significantly decreased and Bax mRNA expression increased in response to DOX treatment. However, pretreatment with fenofibrate restored Bcl-2 and Bax expression to control levels (Figure 8b). Consistently, protein expression of a key downstream effector of apoptosis, cleaved caspase-3, was significantly increased after DOX injury, whereas preincubation with fenofibrate significantly ameliorated the increased caspase-3 activity (Figure 8c). It was also noticed that DOX treatment resulted in a significant increase in reactive oxygen species production, which was attenuated by treatment with fenofibrate (Supplementary Figure S12 online). Download .jpg (.02 MB) Help with files Supplementary Figure 12 To determine whether mice on a 129/SvJ genetic background behave similarly to BALB/c mice during the DOX experiment, we performed a study characterizing the course of DOX nephrotoxicity in both 129/SvJ and BALB/c strains. As shown in Supplementary Figure 13, Supplementary Figure 14, Supplementary Figure 15, Supplementary Figure 16 online, a 6-week treatment of DOX continuously increased proteinuria levels (Supplementary Figure S13A online) and decreased plasma albumin concentrations (Supplementary Figure S13B online) in 129/SvJ mice. Starting from week 4, podocyte foot process effacement appeared and became more severe at week 6 (Supplementary Figure S13C and D online). Blood urea nitrogen and urinary KIM-1 excretion were significantly increased after 4 weeks of DOX treatment and became much higher after 6 weeks of DOX exposure (Supplementary Figure S14 online). Furthermore, podocyte nephrin expression was much lower in the 6-week DOX-treated mice than in the 4-week DOX-treated mice (Supplementary Figure S16 online). Compared with BALB/c mice, in which glomerular sclerosis and tubulointerstitial fibrosis became evident at week 4 (Supplementary Figure S3 online), 129/SvJ mice only exhibited such changes 6 weeks after DOX treatment (Supplementary Figure S15 online). Download .jpg (.05 MB) Help with files Supplementary Figure 13 Download .jpg (.03 MB) Help with files Supplementary Figure 14 Download .jpg (.08 MB) Help with files Supplementary Figure 15 Download .jpg (.06 MB) Help with files Supplementary Figure 16 Increasing evidence suggests that PPAR-α may exert renoprotective effect in the kidney.17.Li S. Basnakian A. Bhatt R. et al.PPAR-alpha ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G.Am J Physiol Renal Physiol. 2004; 287: F990-F998Crossref PubMed Scopus (87) Google Scholar, 18.Li S. Wu P. Yarlagadda P. et al.PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity.Am J Physiol Renal Physiol. 2004; 286: F572-F580Crossref PubMed Scopus (80) Google Scholar, 19.Li S. Gokden N. Okusa M.D. et al.Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF.Am J Physiol Renal Physiol. 2005; 289: F469-F480Crossref PubMed Scopus (118) Google Scholar This study examined the role of PPAR-α in DOX-induced podocyte injury in vivo and in vitro. PPAR-α−/− mice showed more severe urine protein excretion and podocyte foot process effacement than WT mice after DOX treatment. In contrast, fenofibrate treatment effectively reduced proteinuria and ameliorated podocyte foot process effacement in DOX-treated mice. In cultured podocytes, fenofibrate protected against DOX-induced apoptosis. These observations suggest that PPAR-α may participate in the pathogenesis of DOX-induced glomerular podocyte injury and represent a promising preventive target for DOX-associated glomerulopathy. Although PPAR-α activation exerts a beneficial renal effect in DOX-associated renal injury, the underlying mechanisms of how PPAR-α agonist protects against DOX-induced kidney damage remain elusive. A study of diabetic nephropathy showed that fenofibrate markedly attenuated albuminuria and renal fibrosis in a murine model of type 2 diabetes (db/db mice).13.Park C.W. Zhang Y. Zhang X. et al.PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice.Kidney Int. 2006; 69: 1511-1517Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar In contrast, PPAR-α gene deficiency was found to be associated with exacerbated diabetic nephropathy, with more severe albuminuria and worsened renal injury.12.Park C.W. Kim H.W. Ko S.H. et al.Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha.Diabetes. 2006; 55: 885-893Crossref PubMed Scopus (120) Google Scholar In several tubular injury models, PPAR-α activation prevented cisplatin-induced renal tubular injury15.Nagothu K.K. Bhatt R. Kaushal G.P. et al.Fibrate prevents cisplatin-induced proximal tubule cell death.Kidney Int. 2005; 68: 2680-2693Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar and protected renal tubular cells against DOX-induced apoptosis16.Lin H. Hou C.C. Cheng C.F. et al.Peroxisomal proliferator-activated receptor-alpha protects renal tubular cells from doxorubicin-induced apoptosis.Mol Pharma" @default.
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