BASIC INVESTIGATION

Finasteride Reduces Microvessel Density and Expression of Vascular Endothelial Growth Factor in Renal Tissue of Diabetic Rats He-lin Tian, MD, Chao-xian Zhao, MSc, Hai-ying Wu, Zhong-xin Xu, MSc, Li-shun Wei, MSc, Ru-tong Zhao, BSc and Dong-ling Jin, BSc

Abstract: Background: Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of diabetic microvascular complications. Finasteride has been confirmed to decrease VEGF expression in prostate and prostatic suburethral tissue resulting in limiting hematuria from human benign prostatic hyperplasia. The purpose of this study was to evaluate the effects of finasteride on microvessel density (MVD), VEGF protein and mRNA expressions in the renal tissue of diabetic rats. Methods: Diabetic rats induced by streptozotocin were intragastrically given finasteride at 30 mg/kg body weight once a day for 4 weeks. Histomorphologic changes in kidney were observed under light microscope. Immunohistochemistry for CD34 and VEGF on kidney sections was performed to assess MVD and VEGF protein expression in glomeruli of rats, respectively. The VEGF mRNA expression in the renal tissue was examined using reverse transcription polymerase chain reaction analysis. Results: The glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue were significantly increased in diabetic rats and finasteridetreated rats when compared with controls (P , 0.01, P , 0.05). When compared with diabetic rats, the glomerular tuft area, glomerular volume, MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex tissue of finasteride-treated rats were significantly decreased (P , 0.05, P , 0.01). Conclusions: Finasteride reduces the VEGF expression and decreases the MVD in the renal tissue of diabetic rats, suggesting the therapeutic potential of finasteride on diabetic microvascular complications. Key Indexing Terms: Finasteride; Vascular endothelial growth factor; Microvessel density; Kidney; Diabetes mellitus. [Am J Med Sci 2015;349(6):516–520.]

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atients with diabetes with microvascular complications are suffering serious troubles on the quality of life. Pathologic angiogenesis plays an important role in the development and progression of diabetic microvascular complications. Vascular endothelial growth factor (VEGF), a member of the family of heparin-binding growth factors, is very potent in stimulating endothelial cell proliferation and angiogenesis under both physiologic and pathologic conditions.1,2 Finasteride is the first 5a-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH).3,4 Several studies have demonstrated that finasteride can inhibit angiogenesis and reduce prostate bleeding due to decreasing VEGF From the Medical College, Affiliated Hospital, Hebei University of Engineering, Handan, China. Submitted August 30, 2014; accepted in revised form February 2, 2015. Supported by the Natural Science Foundation of Hebei-Shijiazhuang Pharmaceutical Group Foundation (C2011402062). The authors have no conflicts of interest to disclose. Correspondence: He-lin Tian, MD, 83 Congtai Road, Handan 056002, China (E-mail: [email protected]).

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expression in human prostate and prostatic suburethral tissue.5,6 An animal study has shown that finasteride is effective to prevent VEGF expression and microvascular development in the retina of early diabetic rats.7 However, the effects of finasteride on VEGF expression in diabetic renal tissue remain unclear. In this study, the authors evaluated the effects of finasteride on microvessel density, protein and mRNA expressions of VEGF in renal tissue of diabetic rats induced by streptozotocin.

MATERIALS AND METHODS Reagents Finasteride (Lot 20120801) was from Kailun Chemical and Advanced Material Co (Wuhan, China). Streptozotocin (Cat ALX-380–010-G001) was from Alexis Biochemical (San Diego, CA). Monoclonal mouse anti-CD34 antibody (Cat ZM0046) and monoclonal rabbit anti-VEGF antibody (Cat ZA0509) were from Zhongshan Golden Bridge Biotechnology Co (ZSGB Bio, Beijing, China). Trizol reagent (Cat SK1321) was from Sangon Biotech (Shanghai, China). Taq PCR reagent (Cat BS9296) was from Thermo Scientific (Shanghai, China). Diabetic Model Male Wistar rats weighting 230 to 250 g were supplied by Laboratory Animal Center of Hebei (China). All animals were housed in polypropylene cages under 12-hour light/dark cycle with free access to rodent chow and tap water. The rats were intraperitoneally given a single dose of STZ at 65 mg/kg body weight after fasting for 12 hours. STZ was freshly dissolved in cold citrate buffer (pH 4.4) for immediate use within 5 minutes. Rats in which fasting blood glucose level exceeded 17 mmol/L at 72 hours after STZ injection were considered diabetic. Control rats (n 5 7) received an equivalent volume of citrate buffer alone. The diabetic rats were randomly stratified into diabetic model group and finasteride-treated group (n 5 7 per group). The rats in finasteride-treated group were intragastrically given finasteride at 30 mg/kg body weight once a day for 4 weeks. Finasteride was prepared as a fine suspension in 0.5% sodium carboxymethyl cellulose solution in water. The rats in control group and diabetic model group were intragastrically given the same volume of sodium carboxymethyl cellulose solution for 4 weeks. Blood glucose level and body weight of all animals were weekly examined during the whole experiment period. All animals used in this study received humane care in compliance with institutional animal care guidelines. The study was approved by the Local Institutional Committee. Tissue Preparation Fasting blood glucose concentration and body weight of rats were measured after the last administration. All animals were intraperitoneally anesthetized with urethane at 1.5 g/kg

The American Journal of the Medical Sciences



Volume 349, Number 6, June 2015

Finasteride Reduces VEGF in Diabetic Kidney

TABLE 1. Body weight and blood glucose level of rats Body weight, g Groups Control group Diabetic model group Finasteride-treated group

Blood glucose, mmol/L

Day 3

Week 4

Day 3

Week 4

314.0 6 14.4 262.3 6 28.4a 267.8 6 23.1a

354.0 6 20.3 249.8 6 38.3a 244.3 6 32.5a

4.1 6 0.6 20.7 6 3.9a 19.8 6 2.2a

4.9 6 0.7 20.8 6 3.1a 25.3 6 3.6a

Each of the 3 groups contained 7 rats (n 5 7). a P , 0.01 compared with control group.

body weight, and the kidneys were dissected out. The right kidney was weighed and the wet weight index of kidney was calculated as follows: wet weight index 5 wet weight of kidney (in grams)/body weight (in grams) 3 1,000. After the measurement, the right kidney was immediately fixed in 10% neutral formalin solution, routinely embedded in paraffin and consecutively cut into 4 mm sections for histomorphology and immunohistochemistry. The cortex of the left kidney was separated, cut into fine fragments and stored in 270°C refrigerator for reverse transcription polymerase chain reaction (RT-PCR) analysis. Histomorphology Sections from right kidney of rats were stained with hematoxylin and eosin. The histomorphologic changes were observed under light microscope (Olympus, Japan). In each animal, the glomerular tuft areas (Ga) were measured using an image analysis system (BI-2000; Taimeng Software Co, Ltd, Chengdu, China) at a magnification of 3400 as the average area of a total of 70 glomerular profiles. The glomerular volume (Gv) was determined from the glomerular tuft area and calculated as follows: Gv=b/k 3 (Ga)3/2, where b 5 1.38, which is the shape coefficient for spheres (the idealized shape of glomeruli), and k 5 1.1, which is a size distribution coefficient.8 Each section was examined in a blinded fashion. Immunohistochemistry Immunohistochemistry Methods for CD34 and VEGF Sections from right kidney of rats were floated onto polylysine coated slides for immunohistochemical staining using a standard streptavidin peroxidase method. The slides were dewaxed in xylene and dehydrated through a graded series of ethanols. Heat-induced epitope retrieval was performed by immersing the slides in citrate buffer (pH 6.0) and heating at 95°C for 20 minutes, before cooling and rinsing with phosphate-buffered saline (PBS). Endogenous peroxidase activity was quenched by incubation with 3% hydrogen peroxide at

37°C for 10 minutes. Nonspecific protein binding sites were blocked by incubating the sections with normal goat serum. The slides were then incubated with mouse anti-CD34 (1:100) or rabbit anti-VEGF (1:100) primary antibody overnight at 4°C in a humidified chamber. Negative control sections were incubated in PBS without primary antibody. After rinsing with PBS, the tissue-bound primary antibody was detected using biotinylated secondary antibody and horseradish peroxidase biotinylated streptavidin complex (Histostain Plus Kits; ZSGB Bio), with diaminobenzidine (ZSGB Bio) as the chromogen. Finally, the slides were counterstained with hematoxylin, dehydrated and mounted with DPX. Microvessel Counting Any endothelial cell or endothelial cell cluster positively stained for CD34 and clearly separated from the adjacent structures was considered a single, countable microvessel. Microvessels were counted in 10 nonrepeated glomeruli for each slide under light microscope at a magnification of 4003, and the mean of the microvessel counts was recorded as the microvessel density. VEGF Immunostaining Score To evaluate the expression of VEGF protein, we established a score corresponding to the staining intensity and the percentage of positively staining cells. The cell intensity of VEGF expression (I) was graded for absent or weak staining, moderate staining and strong staining of VEGF, and scores of 1, 2 and 3 were assigned, respectively. The percentage of cells with VEGF positive staining (P) was estimated in 10 nonrepeated glomeruli for each slide. Therefore, a VEGF index (I 3 P) was calculated for comparison of VEGF expression among 3 groups.6 Each section was examined in a blinded manner. Semiquantitative RT-PCR Total RNA was extracted from cortex tissue of the left kidney using a Trizol reagent. Single strand cDNA was

FIGURE 1. Histomorphologic changes in the renal tissue of rats (HE staining; magnification, 4003). Note the enlarged glomeruli in diabetic rats (B) and finasteride-treated rats (C) compared with control rats (A). Each of the 3 groups contained 7 rats (n 5 7). Bar: 50 mm. Copyright © 2015 by the Southern Society for Clinical Investigation.

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TABLE 2. Glomerular tuft area, glomerular volume, and wet weight index of kidney of rats Groups Glomerular tuft area (3102), mm2 Glomerular volume (3103), mm3 46.6 6 5.5 59.3 6 4.6a 52.7 6 3.6bc

Control group Diabetic model group Finasteride-treated group

404.9 6 71.3 577.5 6 67.5a 485.8 6 50.8bc

Wet weight index 2.8 6 0.4 5.3 6 0.8a 5.4 6 0.7a

Each of the 3 groups contained 7 rats (n 5 7). a P , 0.01 compared with control group. b P , 0.05. c P , 0.05 compared with diabetic model group.

synthesized using a Taq PCR reagent. All procedures were performed according to the standard protocol provided by the manufacturer. Transcripts of the gene for glyceraldehyde-3phosphate dehydrogenase (GAPDH) were used as an internal control. The following primers were used: VEGF (323 base pairs): 59-TGCACTGGACCCTGGCTTTACTG-39 (forward), 59-GTGCTGGCTTTGGTGAGGTTTGAT-39 (reverse); GAPDH (557 base pairs): 59-GTGAAGGTCGGTGTCAACGGATTT-39 (forward), 59-CACAGTCTTCTGAGAGTGGCAGTGAT-39 (reverse). The reaction mixture was subjected to initial denaturation at 94°C for 5 minutes, followed by 35 cycles of 94°C for 1 minute, 58°C for 1 minute and 72°C for 1 minute. The final extension was done at 72°C for 10 minutes. The PCR product was visualized using ethidium bromide in 2% agarose gel. The integral optical density (IOD) of PCR products was automatically analyzed by a Bio-electrophoresis Image Analysis System (2500R; Tanon Science and Technology Co, Ltd, Shanghai, China). The relative quantification of VEGF mRNA was calculated using the formula: VEGF IOD/GAPDH IOD 3 100%. Each sample was tested in triplicate. Statistical Analysis All values were expressed as mean values 6 SD. Analysis of variance with Student-Newman-Keuls test was used to identify significant differences in multiple comparisons. A level of P , 0.05 was considered statistically significant.

RESULTS Body Weight and Blood Glucose Level In comparison with control rats, the body weights were significantly decreased (P , 0.01), and the blood glucose levels were markedly elevated (P , 0.01) in diabetic rats and finasteride-treated rats at day 3 and the end of week 4 after the development of diabetes. The body weights and blood glucose levels had no significant differences between diabetic rats and finasteride-treated rats (Table 1).

Histomorphologic Observation The renal tubular epithelial cells were swollen, and the glomeruli were enlarged in diabetic rats and finasteride-treated rats at the end of week 4 after the development of diabetes (Figure 1). The glomerular tuft areas, glomerular volumes and wet weight indexes of kidney in diabetic rats and finasteridetreated rats were significantly increased in comparison with control rats (P , 0.01, P , 0.05). When compared with diabetic rats, the glomerular tuft area and glomerular volume in finasteride -treated rats were obviously decreased (P , 0.05), but the wet weight indexes of kidney between 2 groups had no significant difference (Table 2). Immunohistochemistrical Analysis The positive-staining cells of VEGF and CD34 were mainly observed in the glomeruli of rats, and the immunostaining of VEGF and CD34 seemed to be increased in diabetic rats and finasteride-treated rats (Figures 2 and 3). The MVD and VEGF index were markedly increased in glomeruli of diabetic rats and finasteride-treated rats in comparison with control rats (P , 0.01; Table 3). When compared with diabetic rats, the MVD and VEGF index in glomeruli of finasteride-treated rats were significantly decreased (P , 0.05; Table 3). Semiquantitative RT-PCR Analysis The VEGF mRNA levels were significantly increased in the renal cortex tissue of diabetic rats (148.0 6 15.5) and finasteride-treated rats (119.2 6 13.7) in comparison with control rats (100.6 6 12.1; P , 0.01, P , 0.05). But when compared with diabetic rats, the VEGF mRNA level in the renal cortex tissue of finasteride-treated rats was significantly decreased (P , 0.01; Figure 4).

DISCUSSION Microvascular complications resulting from diabetes represent a significant public health burden. Animal models of

FIGURE 2. Immunohistochemistrical staining for CD34 in glomeruli of rats (magnification, 4003). Note CD34 immunostaining concentrated in the glomeruli of rats. (A) Control rats; (B) Diabetic rats; (C) Finasteride-treated rats. Each of the 3 groups contained 7 rats (n 5 7). Bar: 50 mm.

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FIGURE 3. Immunohistochemistrical staining for VEGF in glomeruli of rats (magnification, 4003). Note the positive-staining cells of VEGF mainly located in the glomeruli of rats. (A) Control rats; (B) Diabetic rats; (C) Finasteride-treated rats. Each of the 3 groups contained 7 rats (n 5 7). Bar: 50 mm. VEGF, vascular endothelial growth factor.

diabetes are regarded as very useful tools for studying the pathophysiology of the disease and investigating the effects of hypoglycemic agents. Several methods have been used to produce diabetes in laboratory animals. Commonly used diabetic animal models include spontaneous model, genetic model, and chemicalinduced model.9 Streptozotocin, a diabetogenic agent with pancreatic b-cell toxicity property, is convenient and simple to use for producing chemically induced diabetes models when administered in a single large dose or in repeated low doses for several days. In this study, diabetic rat model was induced by a single intraperitoneal injection of streptozotocin at 65 mg/kg body weight. The typical signs of diabetes such as hyperglycemia, polyphagia, polydipsia, polyuria and body weight loss were present in the rats within 3 days after the development of diabetes. The histomorphology of renal lesions in diabetic rats were also manifesting at the end of week 4 after the development of diabetes. This study showed that the enlarged glomeruli and swollen tubular epithelial cells were noticeable in diabetic rats at the end of week 4 after the development of diabetes. The morphometric analysis of this study demonstrated that the glomerular tuft area, glomerular volume and wet weight index of kidney were markedly increased in diabetic rats when compared with controls. These results indicate that renal impairment may present in the early stage of diabetic rats. Furthermore, this study also found that the MVD, VEGF protein expression in glomeruli and VEGF mRNA expression in the renal cortex were higher in diabetic rats than that in controls. Additionally, a previous study performed at our laboratory found that the glomerular MVD was increased and positively correlated with the VEGF expression in glomeruli of diabetic mice induced by streptozotocin.10 Several clinical trials have reported the elevated VEGF levels in glomeruli, serum and urine of patients with diabetes.11–13 These findings suggest that VEGF may be involved in the microvascular complications associated with diabetes. VEGF is a heparin-bing angiogenic growth factor that displays a high specificity for endothelial cells.14 VEGF potently stimulates microvascular permeability and endothelial cell proliferation and plays an essential role in angiogenesis and

pathogenesis of diabetic microvascular complications. Targeting VEGF may be a beneficial therapeutic strategy for the treatment of early diabetic nephropathy.15 Recently several anti-VEGF pharmacologic agents (such as pegaptanib, bevacizumab, ranibizumab and VEGF Trap-Eye) have been reported to be available and in clinical trials for the treatment of diabetic retinopathy.16 Additionally, interference with transforming growth factor beta and growth hormone/insulin-like growth factor-1 system was shown to prevent manifestations of early experimental diabetic nephropathy.1 The therapeutic effects of other angiogenesis inhibitors (such as tumstatin, endostatin, angiostatin and vasohibin-1) in experimental diabetic nephropathy models have also been reported.17–20 All of these agents could be considered as potential treatments for the early diabetic nephropathy, but further studies are required in humans to establish their possible role in diabetic states. Finasteride is a 5a-reductase inhibitor that acts to repress testosterone to dihydrotestosterone (DHT) and shrink the prostate volume for the clinical application of human BPH.21,22 Several studies have confirmed that finasteride administration in BPH patients suppresses VEGF expression, interferes angiogenesis and reduce MVD in prostate and prostatic suburethral tissue, resulting in the benefit of finasteride in limiting prostate bleeding or hematuria from BPH.6,23,24 Considering the role of VEGF in angiogenesis of diabetic microvascular complications, we performed a prospective evaluation of the effects of finasteride on VEGF expression in the renal tissue of diabetic rats. Results of this study showed that the MVD, expression of VEGF protein in glomerli

TABLE 3. MVD and VEGF index in glomeruli of rats Groups MVD VEGF index Control group Diabetic model group Finasteride-treated group

15.1 6 2.2 23.5 6 2.0a 20.7 6 1.7ab

0.76 6 0.08 1.35 6 0.09a 1.22 6 0.12ab

Each of the 3 groups contained 7 rats (n 5 7). a P , 0.01 compared with control group. b P , 0.05 compared with diabetic model group. MVD, microvessel density; VEGF, vascular endothelial growth factor.

FIGURE 4. VEGF mRNA levels in renal cortex tissue of rats. The VEGF mRNA levels were expressed as percentage of GAPDH in the same group. Columns represent the mean values and vertical bars show the SD. *P , 0.05, **P , 0.01 compared with control group; ##P , 0.01 compared with diabetic model group. Each of the 3 groups contained 7 rats (n 5 7). VEGF, vascular endothelial growth factor.

Copyright © 2015 by the Southern Society for Clinical Investigation.

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and VEGF mRNA in the renal cortex were significantly decreased in diabetic rats after finasteride administration for 4 weeks. Similarly, finasteride has been reported to be effective to prevent the VEGF expression and microvascular development in retina of early diabetic rats induced by alloxan.7 Therefore, it is possible that finasteride has the ability to interfere pathological angiogenesis in several tissues due to its inhibitory effect on VEGF expression. VEGF is regulated by a number of different factors. Androgen has been demonstrated to be a stimulator of VEGF. Previous studies reported that androgen could upregulate the VEGF levels and increase angiogenesis in hyperplastic prostate tissue and prostate cancer.23,25,26 Finasteride has been shown to reduce VEGF levels by blocking the conversion of testosterone to DHT and result in decreasing prostate angiogenesis and the prevalence of prostate cancer.27 In diabetic condition, hyperglycaemia, advanced glycation end products, angiotensin II (Ang II) and a variety of growth factors including transforming growth factor beta, insulin-like growth factor-1, basic fibroblast growth factor as well as hypoxia-inducible factor-1 alpha (HIF-1a), are involved in the upregulation of VEGF expression.20 To the best of our knowledge, this is the first study to examine the effects of finasteride on diabetic nephropathy. The mechanisms of the action of finasteride on decreasing the VEGF expression in diabetic renal tissue are still unclear. According to the findings of a clinical study that the VEGF expression is positively correlated to the HIF-1a expression in prostate tissue from patients with BPH,18 we suppose that the effects of finasteride on VEGF expression might be mediated through HIF-1a. Finasteride could reduce the HIF-1a expression and result in decreasing VEGF expression in diabetic renal tissue. However, further studies are still required to identify the appropriate mechanisms underlying the effects of finasteride on angiogenesis of diabetic microvascular complications.

CONCLUSIONS

This study showed that finasteride reduced the VEGF expression and interfered angiogenesis that significantly decreases the microvessel density in the renal tissue of diabetic rats. These results implicate the therapeutic potential of finasteride on diabetic microvascular complications as well as its potent effect on the treatment of angiogenesis-related diseases. REFERENCES

8. Schrijvers BF, Flyvbjerg A, Tilton RG, et al. A neutralizing VEGF antibody prevents glomerular hypertrophy in a model of obese type 2 diabetes, the Zucker diabetic fatty rat. Nephrol Dial Transplant 2006;21:324–9. 9. Chatzigeorgiou A, Halapas A, Kalafatakis K, et al. The use of animal models in the study of diabetes mellitus. In Vivo 2009;23:245–58. 10. Tian HL, Wei LS, Xu ZX, et al. Microvessel density and expression of vascular endothelial growth factor in glomeruli of diabetic mice. Chin J Pathophysiol 2012;28:358–61. 11. Kanesaki Y, Suzuki D, Uehara G, et al. Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy. Am J Kidney Dis 2005;45:288–94. 12. Chiarelli F, Spagnoli A, Basciani F, et al. Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with type 1 diabetes mellitus: relation to glycaemic control and microvascular complications. Diabet Med 2000;17:650–6. 13. Kim NH, Oh JH, Seo JA, et al. Vascular endothelial growth factor (VEGF) and soluble VEGF receptor FLT-1 in diabetic nephropathy. Kidney Int 2005;67:167–77. 14. De Vriese AS, Tilton RG, Stephan CC, et al. Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane. J Am Soc Nephrol 2001;12:1734–41. 15. Khamaisi M, Schrijvers BF, De Vriese AS, et al. The emerging role of VEGF in diabetic kidney disease. Nephrol Dial Transplant 2003;18:1427–30. 16. Willard AL, Herman IM. Vascular complications and diabetes: current therapies and future challenges. J Ophthalmol 2012;2012:209538. 17. Maeshima Y, Makino H. Angiogenesis and chronic kidney disease. Fibrogenesis Tissue Repair 2010;3:13–7. 18. Yamamoto Y, Maeshima Y, Kitayama H. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 2004;53:1831–40. 19. Ichinose K, Maeshima Y, Yamamoto Y, et al. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 2005;54:2891–903. 20. Karalliedde J, Gnudi L. Endothelial factors and diabetic nephropathy. Diabetes Care 2011;34(suppl 2):S291–6. 21. Parsons JK, Schenk JM, Arnold KB, et al. Finasteride reduces the risk of incident clinical benign prostatic hyperplasia. Eur Urol 2012;62:234–41.

1. De Vriese AS, Tilton RG, Elger M, et al. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol 2001;12:993–10.

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2. Jebreel A, England J, Bedford K, et al. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathathol 2007;88:271–7.

23. Lekas AG, Lazaris AC, Chrisofos M, et al. Finasteride effects on hypoxia and angiogenetic markers in benign prostatic hyperplasia. Urology 2006;68:436–41.

3. Finn DA, Beadles-Bohling AS, Beckley EH, et al. A new look at the 5alpha-reductase inhibitor finasteride. CNS Drug Rev 2006;12:53–76.

24. Memis A, Ozden C, Ozdal OL, et al. Effect of finasteride treatment on suburethral prostatic microvessel density in patients with hematuria related to benign prostate hyperplasia. Urol Int 2008;80:177–80.

4. Stanczyk FZ, Azen CG, Pike MC. Effect of finasteride on serum levels of androstenedione, testosterone and their 5a-reduced metabolites in men at risk for prostate cancer. J Steroid Biochem Mol Biol 2013;138:10–6. 5. Häggström S, Tørring N, Møller K, et al. Effects of finasteride on vascular endothelial growth factor. Scand J Urol Nephrol 2002;36:182–7.

25. Eisermann K, Broderick CJ, Bazarov A, et al. Androgen upregulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site. Mol Cancer 2013;12:7.

6. Pareek G, Shevchuk M, Armenakas NA, et al. The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density: a possible mechanism for decreased prostatic bleeding in treated patients. J Urol 2003;169:20–3.

26. Stewart RJ, Panigrahy D, Flynn E, et al. Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol 2001;165:688–93.

7. Dai XQ, Liu SS, Ni GB, et al. Effects of finasteride on expression of vascular endothelial growth factor and microvascular density in retina of early diabetic rats. Chin J New Drugs Clin Rem 2004;23:199–202.

27. Tay MH, Kaufman DS, Regan MM, et al. Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate. Ann Oncol 2004;15:974–8.

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Finasteride reduces microvessel density and expression of vascular endothelial growth factor in renal tissue of diabetic rats.

Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of diabetic microvascular complications. Finasteride has been conf...
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