Crosstalk between peroxisome proliferator-activated receptor-γ and angiotensin II in renal tubular epithelial cells in IgA nephropathy

Xiao, Jing; Leung, Joseph C.K.; Chan, Loretta Y.Y.; Tang, Sydney C.W.; Lai, Kar Neng

doi:10.1016/j.clim.2009.04.004

Cited by 31 publications

(16 citation statements)

References 42 publications

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“…14,29,43) Consistent with these recent reports, in our experimental conditions, there was obvious evidence of a superiority of the combination therapy over individual therapies in ameliorating the albuminuria and renal structural damage. Xiao et al 43) demonstrated that in human proximal tubular epithelial cells actived with immunoglobulin A (IgA) from patients with IgA nephropathy, dual treatment of rosiglitazone and losartan in vitro provides synergistic effects in reducing intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and AT 1 R expression and nuclear factor-kB (NF-kB) and extracellular signal-regulated kinase (ERK)1/2 activation. Nevertheless, the precise mechanisms whereby the additional renoprotection provided by the combination of a PPARg agonist and an ARB were exerted in vivo required further investigations.…”

Section: Discussionsupporting

confidence: 91%

Losartan and Pioglitazone Ameliorate Nephropathy in Experimental Metabolic Syndrome Rats

Kong

Zhang

et al. 2011

Biological & Pharmaceutical Bulletin

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Metabolic syndrome (MS) has been defined by the presence of a cluster of most dangerous risk factors, such as insulin resistance, hyperinsulinemia, and some combination of dyslipidemia and hypertension.1) Global lifestyle changes, including an increase in caloric intake and a reduction in physical activity, have sharply increased the number of patients with MS.2) Clinical studies reported that MS also increases the risk for proteinuria and chronic kidney disease independent of diabetes and hypertension.3,4) However, the underlying mechanisms and efficient therapy of nephropathy associated with MS are not completely elucidated.Chronic consumption of high-fat, high-sucrose diet induces a MS model in normal rats, which is associated with dyslipidemia, hypertension, obesity, and insulin resistance. 5,6) However, damages of renal structure and function have not been reported in this MS model. In fact, whether high-fat or high-fat, high-sucrose diet produced renal functional and pathological lesions is still conflicting.7,8) Nevertheless, several studies have demonstrated that high salt diet induces slightly hyperinsulinemia, moderately hypertension and renal damages in Sprague-Dawley (SD) rats.9-11) Therefore, we hypothesized that long-term consumption of a high-fat, highsalt diet and sucrose solution in SD rats could induce a suitable animal model that mimics the basic characteristics of human MS and is helpful to understand the pathogenesis and therapy of nephropathy associated with MS.Clinical and experimental studies have shown that losartan (angiotensin II receptor blocker, ARB) and pioglitazone (peroxisome proliferator-activated receptor-g, PPARg agonist) have renoprotective effects in diabetic nephropathy (DN) and non-diabetic renal diseases.12-16) In addition, a recent study demonstrated that losartan and pioglitazone have synergistic renoprotective actions in patients with type 2 DN. 14) However, to our knowledge, there was no study on comparing the effects of losartan and pioglitazone combination therapy with monotherapy in MS nephropathy rats.Vascular endothelial growth factor (VEGF) is an important growth factor involved in neoangiogenesis and vascular trophism. The dysregulation of VEGF signaling system has been identified in a wide variety of renal diseases, such as DN, glomerulonephritis, acute renal failure, chronic renal disease, and so on. [17][18][19] Qin et al. 13) suggested that losartan attenuates the overexpression of VEGF in DN rats. Lee et al. 20) demonstrated that pioglitazone has beneficial effects on DN in Otsuka-Long-Evans-Tokushima-Fatty rats by reducing the VEGF expression. Thus, we speculated that both drugs might improve renal damage in this MS model through attenuating dysregulation of the VEGF expression.Therefore, the purposes of this study were: first, to establish a suitable animal model of nephropathy associated with MS; second, to evaluate the possible benefits of losartan and pioglitazone in this experimental MS nephropathy rats; third, to assess whether the combination ...

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Section: Discussionsupporting

confidence: 91%

Losartan and Pioglitazone Ameliorate Nephropathy in Experimental Metabolic Syndrome Rats

Kong

Zhang

et al. 2011

Biological & Pharmaceutical Bulletin

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“…15 PPAR γ agonists also downregulated AT 1 R expression in proximal tubular epithelial and vascular smooth muscle cells with inhibition of ERK1/2 activation and attenuated NF-κ B activation. 16–18 Further, in AT 1a receptor-overexpressing HEK 293 cells, PPAR γ agonist stimulated this receptor to induce endogenous β arr1/2 recruitment and AT 1a R internalization without Gq protein activation. 19 In our study, we did not detect change of AT 1 R expression, but can not exclude a potential effect of PPAR γ on AT1R activity through other pathways, such as G protein signaling.…”

Section: Discussionmentioning

confidence: 98%

Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis

Matsushita

Yang

Mysore

et al. 2016

Laboratory Investigation

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We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.

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“…Lee et al [26] showed that pretreatment with rosiglitazone reduced BUN levels and decreased NF-ĸB activity, macrophage infiltration, and expression of TNF-α and ICAM-1 in cisplatin nephrotoxicity. Xiao et al [27] showed that rosiglitazone could attenuate excessive inflammation in activated human proximal tubular epithelial cells in IgAN through the inhibition of ERK1/2 activation. Rosiglitazone has also been shown to inhibit proteinuria and BUN levels, and reduce ECM apposition through the down-regulation of transforming growth factor-β (TGF-β), PAI-1, and fibronectin expression in rats with Thy1 glomerular nephritis [28].…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

Wang¹,

Chen²,

Zhong³

et al. 2011

Am J Nephrol

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Background: Inflammation may play an important role in the pathogenesis of kidney disease. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as rosiglitazone, have been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators. The purpose of this study was to examine the effects of rosiglitazone on lipopolysaccharide (LPS)-induced kidney inflammation and to explore the mechanism of its renoprotection. Methods: Mice were treated with LPS with or without pretreatment with rosiglitazone. Blood urea nitrogen (BUN), creatinine levels, the urinary albumin-to-creatinine ratio, macrophage infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, PPAR-γ expression, and NF-ĸB and PPAR-γ activity were investigated. HK-2 cells were maintained under defined in vitro conditions, treated with either rosiglitazone and/or the PPAR-γ antagonist GW9662, and then stimulated with LPS. MCP-1, IL-8, IL-6, NF-ĸB activity and PPAR-γ expression were investigated. Results: Compared to the LPS only group, pretreatment with rosiglitazone in vivo significantly attenuated the BUN levels macrophage infiltration, MCP-1 overexpression and NF-ĸB activity (p < 0.05). Rosiglitazone also restored PPAR-γ expression and protein activity, which were reduced significantly in the LPS only group (p < 0.05). Furthermore, in the LPS-stimulated HK-2 cells, rosiglitazone downregulated MCP-1, IL-8 and IL-6 expression as well as NF-ĸB activation and increased PPAR-γ expression (p < 0.05). These effects were diminished by GW9662. Conclusion: These results showed that pretreatment with rosiglitazone could attenuate kidney inflammation through the activation of PPAR-γ, suppression of MCP-1 overproduction and NF-ĸB activation. Rosiglitazone had a protective effect via a PPAR-γ-dependent pathway in LPS-treated HK-2 cells.

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Crosstalk between peroxisome proliferator-activated receptor-γ and angiotensin II in renal tubular epithelial cells in IgA nephropathy

Cited by 31 publications

References 42 publications

Losartan and Pioglitazone Ameliorate Nephropathy in Experimental Metabolic Syndrome Rats

Losartan and Pioglitazone Ameliorate Nephropathy in Experimental Metabolic Syndrome Rats

Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis

Inhibitory Effects of Rosiglitazone on Lipopolysaccharide-Induced Inflammation in a Murine Model and HK-2 Cells

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