Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells

Lebeau, Catherine; Arlt, Volker M.; Schmeiser, Heinz H.; Boom, Alain; Verroust, P; Devuyst, Olivier; Beauwens, Renaud

doi:10.1046/j.1523-1755.2001.00938.x

Cited by 89 publications

(67 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…45 Furthermore, aristolochic acid isolated from Aristolochia fangchi was shown to induce cellular injury and apoptosis in proximal tubular (LLC-PK1) epithelial cell lines. [46][47][48][49] The results described in this study introduce the first in vivo evidence that the previously reported OA-evoked increases in urinary Na þ output are in part mediated via inhibition of Na þ reabsorption and increases in proximal tubular Na þ secretion. The study provides the first in vitro evidence that OA does not exhibit toxicity in kidney and liver cell lines and implicates the proximal tubule in the natriuretic effects of OA.…”

supporting

confidence: 66%

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

et al. 2012

View full text Add to dashboard Cite

Studies indicate that Syzygium spp-derived oleanolic acid (OA) enhances renal function of streptozotocin (STZ)-induced diabetic rats as evidenced by its reversal of the previously reported inability of the kidney to excrete Na þ in these animals. We postulated that OA influences Na þ excretion in the proximal tubule, the site where two-thirds of filtered NaCl is reabsorbed through a process mediated by transport proteins. Therefore, the study investigated the effects of OA on proximal tubular Na þ handling in male Sprague-Dawley rats using renal lithium clearance (C Li ). Renal C Li has been used widely in animal and clinical studies to assess proximal tubular function. Sub-chronic doses of OA were administered to rats twice every third day for 5 weeks. Rats treated with deionized water served as control animals. Cytotoxicity of OA on kidney and liver cell lines was assessed by the MTT and comet assays. OA increased Na þ excretion of conscious male Sprague-Dawley rats from week 3 to week 5. By the end of the 5-week experimental period, OA treatment significantly reduced (p < 0.05) plasma creatinine concentration of STZ-induced diabetic rats with a concomitant elevation in glomerular filtration rate (GFR). Acute OA infusion was also associated with increases in fractional excretion of sodium (FE Na ) and lithium (FE Li ) in anesthetized rats in the absence of significant changes in GFR. The MTT assay studies demonstrated that OA increased the metabolic activity of kidney and liver cell lines. Taken together with previous observations, this study implicates the proximal tubule in OA-evoked increases in urinary Na þ output.

show abstract

supporting

confidence: 66%

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Simvastatin, used as an example of the statin class, inhibited the uptake of FITC-BSA and FITC--␤ 2 -microglobulin but not of FITC-inulin-a marker of fluidphase fluid endocytosis. Albumin and ␤ 2 -microglobulin bind to the cubilin/megalin receptor system that is present in OK cells and in clathrin-coated pits in the brush border of proximal tubular epithelial cells (27,34). These receptors are responsible for the binding and internalization of multiple proteins from the glomerular filtrate, including albumin, peptide hormones, and vitamin binding proteins (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…Albumin and ␤ 2 -microglobulin are absorbed by receptormediated endocytosis in OK cells, whereas the polysaccharide inulin is taken up by fluid-phase endocytosis (26,27). As shown in Figure 3, the uptake of FITC-BSA (5 or 50 mg/L) and FITC-␤ 2 -microglobulin (2.5 or 25 mg/L) was inhibited bỹ 75% (P Ͻ 0.001) compared with control after incubation with simvastatin for 24 h. However, the internalization of FITCinulin (500 mg/L) was unaffected, indicating that receptormediated endocytosis was specifically inhibited by statins.…”

Section: Inhibition Of Receptor-mediated Endocytosis Of Low Molecularmentioning

confidence: 99%

Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Sidaway¹,

Davidson

McTaggart

et al. 2004

Journal of the American Society of Nephrology

140

105

View full text Add to dashboard Cite

Abstract. Renal proximal tubule cells are responsible for the reabsorption of proteins that are present in the tubular lumen. This occurs by receptor-mediated endocytosis, a process that has a requirement for some GTP-binding proteins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase used for the therapeutic reduction of cholesterol-containing plasma lipoproteins. However, they can also reduce intracellular levels of isoprenoid pyrophosphates that are derived from the product of the enzyme, mevalonate, and are required for the prenylation and normal function of GTP-binding proteins. The hypothesis that inhibition of HMG-CoA reductase in renal proximal tubule cells could reduce receptor mediated-endocytosis was therefore tested. Five different statins inhibited the uptake of FITC-labeled albumin by the proximal tubule-derived opossum kidney cell line in a dose-dependent manner and in the absence of cytotoxicity. The reduction in albumin uptake was related to the degree of inhibition of HMG-CoA reductase. Simvastatin (e.g., statin) inhibited receptor-mediated endocytosis of both FITC-albumin and FITC-␤ 2 -microglobulin to similar extents but without altering the binding of albumin to the cell surface. The effect on albumin endocytosis was prevented by mevalonate and by the isoprenoid geranylgeranyl pyrophosphate but not by cholesterol. Finally, evidence that the inhibitory effect of statins on endocytosis of proteins may be caused by reduced prenylation and thereby decreased function of one or more GTP-binding proteins is provided. These data establish the possibility in principle that inhibition of HMG-CoA reductase by statins in proximal tubule cells may reduce tubular protein reabsorption.Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, the major rate-limiting step of the sterol pathway (1). The statins are widely used for the therapeutic reduction of cholesterol-containing atherogenic lipoproteins (2-4). This is brought about as a result of depletion of intracellular mevalonate leading to reduction of the regulatory sterol pool, which in turn causes upregulation of HMGCoA reductase and other enzymes of the sterol pathway, most importantly the LDL receptors principally in the liver (5-7). However, a range of additional effects of statins on cells that are independent of cholesterol homeostasis has been described; these include, proliferation (8), signal transduction (9), and apoptosis (10). Many of these cholesterol-independent effects of statins have been shown to result from depletion of mevalonate and its nonsterol metabolites, particularly the isoprenoid pyrophosphates, such as farnesol pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), that are required for the posttranslation modification of a variety of cell proteins, including the superfamily of small GTP-binding proteins (11)(12)(13). Endocytosis is one cell function that requires multiple GTP-binding proteins (14,15) a...

show abstract

“…21 On the other hand, specific DNA damage due to AA in urothelial cells and cell-specific alterations at the transcription level of proteins might impair physiological processes. 22 This may not only be of primary importance in explaining the rapidly progressive nature of AAN but also a potential mechanism on the seeming tissue specificity of the AAN-associated oncogenesis compared to the widespread occurrence of AA-DNA adducts.…”

Section: Dear Sirmentioning

confidence: 99%

Aristolochic acid (AA)‐DNA adduct as marker of AA exposure and risk factor for AA nephropathy‐associated cancer

Arlt¹,

Alunni-Perret²,

Quatrehomme³

et al. 2004

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Aristolochic acid impedes endocytosis and induces DNA adducts in proximal tubule cells

Abstract: The present data support the involvement of AA in the early PT dysfunction found in CHN; furthermore, they suggest a causal relationship between DNA adduct formation, decreased megalin expression, and inhibition of receptor-mediated endocytosis of LMWP.

Cited by 89 publications

References 39 publications

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Aristolochic acid (AA)‐DNA adduct as marker of AA exposure and risk factor for AA nephropathy‐associated cancer

Contact Info

Product

Resources

About