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Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy.

ABSTRACT: The combination of Chinese herbs, Astragali Radix and Angelicae Sinensis Radix, could alleviate renal interstitial fibrosis. Astragaloside IV (AS-IV) and ferulic acid (FA) are the two major active constituents in this combination. In this study, we employed rats with unilateral ureteral obstruction to determine whether AS-IV and FA have the same renoprotective effects and investigated the mechanisms of this action.Renal pathological changes were evaluated after treatment with AS-IV, FA or AS-IV + FA (AF) for 10 days. Meanwhile, the expression of transforming growth factor ?(1) (TGF-?(1) ), fibronectin, ?-smooth muscle actin (?-SMA), phosphorylation of c-Jun NH(2) -terminal kinase (p-JNK) and nitric oxide (NO) production in kidney were determined. The expressions of fibronectin, ?-SMA, mitogen-activated protein kinases [JNK, extracellular signal-regulated kinases (ERK), P38] in TGF-?(1) -treated NRK-49F cells or interleukin-1-treated HK-2 cells after AS-IV, FA or AF were assessed.AF alleviated the infiltration of mononuclear cells, tubular atrophy and interstitial fibrosis; reduced the expression of fibronectin, ?-SMA, TGF-?(1) and p-JNK; and dramatically increased the production of NO in obstructed kidneys. Neither AS-IV nor FA alone improved renal damage, but both increased NO production. AF inhibited ?-SMA and fibronectin expression in NRK-49F or HK-2 cells. Furthermore, AF significantly inhibited IL-1?-induced JNK phosphorylation, without affecting ERK or P38 phosphorylation. Neither AS-IV nor FA alone had any effect on the cells.AS-IV synergizes with FA to alleviate renal tubulointerstitial fibrosis; this was associated with inhibition of tubular epithelial-mesenchymal transdifferentiation (EMT) and fibroblast activation, as well as an increase in NO production in the kidney.

SUBMITTER: Meng LQ

PROVIDER: S-EPMC3081123 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy.

Meng L Q LQ Tang J W JW Wang Y Y Zhao J R JR Shang M Y MY Zhang M M Liu S Y SY Qu L L Cai S Q SQ Li X M XM

British journal of pharmacology 20110401 8

<h4>Background and purpose</h4>The combination of Chinese herbs, Astragali Radix and Angelicae Sinensis Radix, could alleviate renal interstitial fibrosis. Astragaloside IV (AS-IV) and ferulic acid (FA) are the two major active constituents in this combination. In this study, we employed rats with unilateral ureteral obstruction to determine whether AS-IV and FA have the same renoprotective effects and investigated the mechanisms of this action.<h4>Experimental approach</h4>Renal pathological ch ...[more]

PMID: 21232035

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Project description:Proteinuria is an important cause of tubulointerstitial damage. Anti-proteinuric interventions are not always successful, and residual proteinuria often leads to renal failure. This indicates the need for additional treatment modalities by targeting the harmful downstream consequences of proteinuria. We previously showed that proteinuria triggers renal lymphangiogenesis before the onset of interstitial inflammation and fibrosis. However, the interrelationship of these interstitial events in proteinuria is not yet clear. To this end, we specifically blocked lymphangiogenesis (anti-VEGFR3 antibody), monocyte/macrophage influx (clodronate liposomes) or lymphocyte and myofibroblast influx (S1P agonist FTY720) separately in a rat model to investigate the role and the possible interaction of each of these phenomena in tubulointerstitial remodeling in proteinuric nephropathy. Proteinuria was induced in 3-month old male Wistar rats by adriamycin injection. After 6 weeks, when proteinuria has developed, rats were treated for another 6 weeks by anti-VEGFR3 antibody, clodronate liposomes or FTY720 up to week 12. In proteinuric rats, lymphangiogenesis, influx of macrophages, T cells and myofibroblasts, and collagen III deposition and interstitial fibrosis significantly increased at week 12 vs week 6. Anti-VEGFR3 antibody prevented lymphangiogenesis in proteinuric rats, however, without significant effects on inflammatory and fibrotic markers or proteinuria. Clodronate liposomes inhibited macrophage influx and partly reduced myofibroblast expression; however, neither significantly prevented the development of lymphangiogenesis, nor fibrotic markers and proteinuria. FTY720 prevented myofibroblast accumulation, T-cell influx and interstitial fibrosis, and partially reduced macrophage number and proteinuria; however, it did not significantly influence lymphangiogenesis and collagen III deposition. This study showed that proteinuria-induced interstitial fibrosis cannot be halted by blocking lymphangiogenesis or the influx of macrophages. On the other hand, FTY720 treatment did prevent T-cell influx, myofibroblast accumulation and interstitial fibrosis, but not renal lymphangiogenesis and proteinuria. We conclude that tubulointerstitial fibrosis and inflammation are separate from lymphangiogenesis, at least under proteinuric conditions.

Project description:BackgroundDiabetic nephropathy (DN) is one of the leading causes of end-stage kidney disease. Recently, there is no specific drug available to block the kidney damage. Astragaloside IV (AS-IV) is a major active component of Astragalus membranaceus (Fisch) Bge and has been demonstrated to benefit the kidney functions. This study explores the potential pharmacological action of AS-IV in DN of rats.MethodsMale Sprague-Dawley rats were fed with high-fat diet and injected with streptozotocin to induce diabetes. The diabetic rats were randomized and treated with vehicle or AS-IV (80 mg/kg) daily by gavage for 12 weeks as the DN or AS-IV group, respectively. The normal control rats were fed with normal chow and injected with vehicles (n = 8 per group). These rats were monitored for diabetes- and kidney function-related measures. The expression profiles of gene mRNA transcripts in the kidney tissues were analyzed by RNA-seq and quantitative RT-PCR. The levels of advanced glycation end products (AGEs), IL-1β, and IL-18 in the serum samples and kidney tissues were quantified by ELISA. The levels of collagen IV (COL-4) and fibronectin (FN) expression in kidney tissues were examined by immunohistochemistry and Western blot.ResultsIn comparison with the DN group, AS-IV treatment significantly reduced blood glucose levels, food and water consumption, 24 h urine, renal index values, 24 h urine total proteins, blood urea nitrogen (BUN) levels, and creatinine clearance rates (CCR), accompanied by minimizing the DN-induced early kidney damages, fibrosis, and microstructural changes. Furthermore, AS-IV treatment significantly modulated the DN-altered gene transcription profiles in the kidney of rats, particularly for inflammation-related genes, including the nucleotide-binding oligomerization domain-like receptor signaling, which was validated by quantitative RT-PCR. AS-IV treatment significantly decreased the levels of serum and kidney AGEs, IL-1β, and IL-18 expression and fibrosis indexes in the kidney of rats.ConclusionAS-IV treatment ameliorated the severity of DN by inhibiting inflammation-related gene expression in the kidney of rats.

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Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy.

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Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy.

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