Protective effects of dietary phytoestrogens in chronic renal disease☆☆☆★
Article Outline
Abstract
Phytoestrogens are naturally occuring plant compounds that are present primarily in soybeans as isoflavones and in flaxseed as lignans. Because of their structural similarity to endogenous estrogens, phytoestrogens bind to both estrogen receptors (ER)-α and β (but more strongly to ER-β) and exert estrogen-like effects. There is increasing evidence that dietary phytoestrogens have a beneficial role in chronic renal disease. Nutritional intervention studies have shown that consumption of soy-based protein and flaxseed reduces proteinuria and attenuates renal functional or structural damage in animals and humans with various forms of chronic renal disease. It is not clear which component(s) of the soybean or flaxseed is (are) responsible for the protective effects observed in experimental animals and in limited studies in humans. Vegetable protein has been shown to have a beneficial effect on renal disease in animals and humans. Thus, the role of soy and flaxseed cannot be ruled out. Isoflavones and lignans are readily absorbed from the gut and converted to active metabolites, which may be partly responsible for the beneficial renal effects of soy protein and flaxseed. In addition, an interaction between type of protein and phytoestrogens is also possible. The biological actions of isoflavones and lignans have been well defined in different cell types in vitro and also in vivo, but how these compounds might reduce renal injury remains to be elucidated. Possible mechanisms include inhibition of cell growth and proliferation via ER-mediated mechanisms or non–ER-mediated pathways through inhibition of tyrosine protein kinases, modulation of growth factors involved in extracellular matrix synthesis and fibrogenesis, inhibition of cytokine-induced activation of transcription factors, inhibition of angiogenesis, antioxidative action, suppression of platelet activating factor and platelet aggregation, and immunomodulatory activity. To date, clinical trials in humans are few, of relatively short duration, and involve a small number of patients. Prospective randomized trials are needed to evaluate the long-term safety and effectiveness of dietary phytoestrogens on renal disease progression in patients with chronic renal failure. © 2001 by the National Kidney Foundation, Inc.
No full text is available. To read the body of this article, please view the PDF online.
References
- . A low nitrogen diet with protein of high biological value for severe chronic uremia. Lancet. 1964;1:1000–1003
- . Dietary treatment of chronic renal failure. Experience with a modified Giovanetti diet. Nephron. 1965;2:129–147
- . Metabolic studies of low protein diets in uremia. I. Nitrogen and potassium. Medicine. 1973;52:583–595
- . Effects of dietary therapy on urmeic symptoms and complications. In: Giovannetti S editors. Nutritional Therapy of Chronic Renal Failure. Boston, MA: Kluwer Academic; 1989;p. 235–240
- . Nutritional therapy of the uremic patient. In: ed 5. Brenner BM editors. The Kidney. Philadelphia, PA: Saunders; 1996;p. 2382–2423
- Should protein intake be restricted in pre dialysis patients. Kidney Int. 1999;55:771–779
- . Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis of aging, renal ablation, and intrinsic renal disease. N Engl J Med. 1982;307:652–659
- . Role of dietary factors in the progression of chronic renal disease. Kidney Int. 1983;24:579–587
- Prospective randomized trial of early dietary protein restriction in chronic renal failure. Lancet. 1984;2:1291–1296
- The effect of a ketoacid-amino acid supplement to a restricted diet on the progression of chronic renal failure. N Engl J Med. 1984;311:623–629
- The effect of protein restriction on the progression of renal insufficiency. N Engl J Med. 1989;321:1773–1777
- Restriction of dietary protein and progression of renal failure in diabetic nephropathy. Lancet. 1989;2:1411–1414
- . Low protein diets in renal disease. Diabetes Care. 1991;14:856–866
- Controlled low protein diets in chronic renal insufficiency: Meta-analysis. BMJ. 1992;304:216–220
- The effects of dietary protein restriction on the progression of diabetic and non-diabetic renal disease: A meta-analysis. Ann Intern Med. 1996;124:627–632
- . Metabolic consequences of differing protein diets in experimental renal disease. Eur J Clin Invest. 1987;17:117–122
- . Effect of varying quantity and quality of dietary protein intake in experimental renal disease in rats. Nephron. 1987;46:83–90
- Effects of a vegetarian, supplemented diet on renal function, proteinuria, and glucose metabolism in patients with “overt” diabetic nephropathy and renal insufficiency. Contrib Nephrol. 1988;65:87–94
- Predominantly vegetarian diet in patients with incipient and early clinical diabetic nephropathy: Effects on albumin excretion rate and nutritional status. Diabet Med. 1991;8:949–953
- . Soy protein diet therapy in renal disease. Nephron. 1998;78:328–331
- The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol. 1988;43:B5–B12
- Diet and the suitability of the male Fischer 343 rat as a model for aging research. J Gerontol. 1993;48:B27–B32
- Effect of dietary soy protein and genistein on disease progression in mice with polycystic kidney disease. Am J Kidney Dis. 1998;31:55–61
- . Dietary soy protein effects on inherited polycystic kidney disease are influenced by gender and protein level. J Am Soc Nephrol. 1999;10:300–308
- Soy protein modification of rat polycystic kidney disease. Am J Physiol. 1998;274(3Pt2):F541–F549
- Modification of polycystic kidney disease and fatty acid status by soy protein diet. Kidney Int. 2000;57:159–166
- Effect of vegetarian soy diet on hyperlipidaemia in nephrotic syndrome. Lancet. 1992;339:1131–1134
- Treatment of proteinuric patients with a vegetarian soy diet and fish oil. Clin Nephrol. 1993;40:315–320
- Comparison of a vegetable-based (soya) and an animal-based low-protein diet in predialysis chronic renal failure patients. Nephron. 1998;79:173–180
- Effects of soy protein on renal function and proteinuria in patients with type 2 diabetes. Am J Clin Nutr. 1998;68(Suppl 6):1347S–1353S
- Abrogation of MRL/lpr lupus nephritis by dietary flaxseed. Am J Kidney Dis. 1993;22:326–332
- . Murine models of systemic lupus erythematosus. Adv Immunol. 1985;37:269–290
- Effects of flaxseed and flax oil diets in a rat-5/6 renal ablation model. Am J Kidney Dis. 1995;25:320–329
- Flaxseed ameliorates interstitial nephritis in rat polycystic kidney disease. Kidney Int. 1999;55:417–423
- Flaxseed: A potential treatment for lupus nephritis. Kidney Int. 1995;48:475–480
- Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology. 1978;103:1860–1867
- . Interaction of naturally occurring non-steroidal estrogens with expressed with recombinant human estrogen receptor. J Steroid Biochem Mol Biol. 1994;49:153–160
- . Lignification in plant cell walls. In: Jeon KW editors. International Review of Cytology. vol 176:San Diego, CA: Academic; 1997;p. 87–132
- Soya—A dietary source of the non-steroidal oestrogen equol in humans and animals. J Endocrinol. 1984;102:49–56
- Genistein and daidzein, and their β-glycoside conjugates: Anti-tumor isoflavones in soy bean foods from American and Asian diets. J Agric Food Chem. 1993;41:1961–1967
- . Isoflavone content in commercial soybean foods. J Agric Food Chem. 1994;42:1666–1673
- . Isoflavone composition of American and Japanese soybean in Iowa: Effects of variety, crop year, and location. J Agric Food Chem. 1994;42:1674–1677
- . Legumes and Legume Products. In: Washington, DC: United States Department of Agriculture; 1986;p. 1–156
- . Soy protein in relation to human protein and amino acid nutrition. J Am Diet Assoc. 1991;91:828–835
- Mammalian lignan production from various foods. Nutr Cancer. 1991;16:43–52
- Variability in anticancer lignan levels in flaxseed. Nutr Cancer. 1997;27:26–30
- Isotope dilution gas chromatographic-mass spectrometric method for the determination of isoflavonoids, coumestrol, and lignans in food samples. Anal Biochem. 1996;233:169–180
- . Grain processing and nutrition. Crit Rev Food Sci Nutr. 2000;40:309–326
- . Mammalian lignans and phyto-estrogens. Recent studies on their formation, metabolism and biologic role in health and disease. In: Rowland I editors. Role of the Gut Flora in Toxicity and Cancer. Basel, Switzerland: Karger; 1988;p. 315–345
- . Production and metabolism of lignans by the human faecal flora. J Appl Bacteriol. 1985;58:37–43
- . The excretion of lignans in rats: evidence for an intestinal bacterial source for this new group of compounds. FEBS Lett. 1981;123:337–342
- Interindividual variation in metabolism of soy isoflavones and lignans: Influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000;36:27–32
- Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol. 1994;142:251–259
- Quantitative determination of lignans and isoflavones in plasma of omnivorous and vegetarian women by isotope-dilution gas chromatography-mass spectrometry. Scand J Clin Lab Invest. 1993;53(suppl 215):5–18
- . Plasma concentrations of phyto-oestrogens in Japanese men. Lancet. 1993;342:1209–1210
- . Human metabolism of mammalian lignan precursors in raw and processed flaxseed. Am J Clin Nutr. 1999;69:549–555
- Urinary lignan and isoflavonoid excretion in premenopausal women consuming flaxseed powder. Am J Clin Nutr. 1994;60:122–128
- Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr. 1995;61:62–68
- Dose-dependent production of mammalian lignans in rats and in vitro from the purified precursor secoisolariciresinol diglycoside in flaxseed. J Nutr. 1996;126:2012–2019
- . Phytoestrogens: The biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr. 1998;68:1333S–1348S
- . Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab. 1998;83:2223–2235
- In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol. 1993;45:399–405
- Interaction of estrogenic chemicals and phytoestrogens with estrogen receptorβ. Endocrinology. 1998;139:4252–4263
- . Immunolocalisation of oestrogen receptor beta (ERβ) in human tissues. J Mol Endocrinol. 2000;24:145–155
- Antiproliferative activity of mammalian lignan derivatives against the human breast carcinoma cell line, ZR-75-1. Cancer Invest. 1990;8:595–601
- . The effect of flaxseed supplementation on the initiation and promotional stages of mammary tumorigenesis. Nutr Cancer. 1992;17:153–159
- . Isoflavones inhibit the growth of human prostate cancer cells in culture. Proc Am Assoc Cancer Res. 1992;33:57–64
- Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 1993;53:5815–5821
- . Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer. 1997;27:31–40
- . Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis. 1996;17:271–275
- Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci U S A. 1993;90:2690–2694
- Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987;262:5592–5595
- Mechanisms of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem Pharmacol. 1990;39:187–193
- Effect of genistein on topoisomerase activity and on the growth of [Val 12] Ha-ras-transformed NIH 3T3 cells. Biochem Biophys Res Commun. 1988;157:183–189
- Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res. 1989;49:5111–5117
- . Mechanisms of action of the soy isoflavone genistein: Emerging role for its effects via transforming growth factor β signaling pathways. Am J Clin Nutr. 1998;68(suppl):1418S–1425S
- Inhibition of tumor promoter-induced hydrogen peroxide formation in vitro and in vivo by genistein. Nutr Cancer. 1993;20:1–12
- Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proc Soc Exp Biol Med. 1995;208:124–130
- . The antioxidant activity of genistein in vitro. J Nutr Biochem. 1995;6:481–485
- Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metablites enterodiol and enterolactone. Mol Cell Biochem. 1999;202:91–100
- Antioxidant action and potential antidiabetic properties of an isoflavonoid-containing soyabean phytochemical extract (SPE). Phytother Res. 1999;13:601–608
- . Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses. Mol Pharmacol. 1991;39:475–480
- Thombin-induced human platelet aggregation is inhibited by protein tyrosine-kinase inhibitors, ST638 and genistein. FEBS Lett. 1992;309:10–14
- Inhibition of platelet activation by tyrosine kinase inhibitors. Biochem Pharmacol. 1992;44:881–888
- . The effects of genistein on platelet function are due to thromboxane receptor antagonism rather than inhibition of tyrosine kinase. Prostaglandins Leukot Essent Fatty Acids. 1992;48:379–384
- . Kadsurenone and other related lignans as antagonists of platelet-activating factor receptor. Methods Enzymol. 1990;187:446–454
- Inhibition of nitric oxide (NO) production in murine macrophages by flavones. Biochem Pharmacol. 1995;50:1031–1035
- . Inhibition of bovine mononuclear cell proliferation, interleukin-2 synthesis, protein-tyrosine kinase and leukotiene-B(4) production by a protein-tyrosine kinase inhibitor, genistein. Vet Immunol Immunopathol. 1993;38:113–122
- Tyrosine kinase dependent expression of TGF-beta induced by stretch in mesangial cells. Kidney Int. 1997;51:1028–1036
- Involvement of PDGF in pressure-induced mesangial cell proliferation through PKC and tyrosine kinase pathways. Am J Physiol. 1999;277(1Pt2):F105–F112
- Atherogenic lipoproteins enhance mesangial cell expression of platelet-derived growth factor: role of protein tyrosine kinase and cyclic AMP-dependent protein kinase. J Lab Clin Med. 1998;131:456–465
- . Dual regulation of IL-1β-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kB and AP-1. Am J Physiol. 1996;270(1 Pt 2):F123–F130
- . Effect of tyrosine kinase inhibitor, genistein, on interleukin-1 stimulated PGE2 production in mesangial cells. Biochem Biophys Res Commun. 1990;73:718–724
☆ †Research Chemist, Phytonutrients Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD.
☆☆ ‡Professor of Medicine, Division of Renal Diseases and Hypertension, George Washington University Medical Center, Washington, DC.
★ Address reprint requests to Manuel T. Velasquez, MD, Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW, Washington, DC 20037.
PII: S1051-2276(01)70036-2
doi:10.1016/S1051-2276(01)70036-2
© 2001 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

