**4. Improvement of antioxidantive status in diabetic nephropathy**

There are many evidences suggest that ROS play an important role in the pathogenesis of diabetic nephropathy (Rosen et al., 2001). To prevent the development and progression of diabetic nephropathy, it would be effective in combing the strategies to prevent overproduc‐ tion of ROS and to increase the removal of preformed ROS. (Ha et al., 2008). Some natural products were proved to possess the ability to decelerate diabetic nephropathy via reducing oxidative status. The flower of *Hibiscus sabdariffa*Linnaeus calyx (family Malvaceae, local name Karkaday) is commonly used in cold and hot beverages and as a supplement due to its perceived potential of health benefits. The flower extract has been reported to decrease blood pressure, and have antitumor characteristics as well as immune-modulating and anti‐ leukemic effects (Haji Faraji and Haji Tarkhani, 1999; Tseng et al., 2000). *Hibiscus sabdariffa*L. extract contains polyphenolic acids, flavonoids, protocatechuic acid (PCA) and anthocya‐ nins. *Hibiscus sabdariffa*L. extract has been found to contain various polyphenols and was shown to have antioxidative potential to inhibit the development of atherosclerosis in cho‐ lesterol-fed rabbits, LDL oxidation and ox-LDL-mediated macrophage apoptosis (Chen et al., 2003; Chang et al., 2006). Wang et al. (2009) demonstrated that aqueous extract of *Hibis‐ cus sabdariffa* L. (HSE) is capable of increasing catalase and glutathione activities significantly in diabetic kidney. In histological examination, HSE improves hydropic change of renal proximal convoluted tubules in diabetic rats. HSE was also revealed to up-regulate Akt/Bad/ 14-3-3 and NF-κB-mediated transcription in diabetic nephropathy. Luteolin is a plant-de‐ rived flavonoid, it has various biological activities including anti-inflammatory (Jang et al., 2008), antimutagenic, and antitumorigenic properties (Ross and Kasum, 2002). It also pos‐ sesses direct antioxidant activity (L´opez-L´azaro, 2009), and may be useful in treatment of many chronic disease associated with oxidative stress, such as cardiovascular diseases (McCord, 1985; Jeroudi et al., 1994), liver diseases (Comporti, 1985; Poli et al., 1987), diabetes (Oberley, 1988), and aging (Harman, 1981). Wang et al. (2011) demonstrated that luteolin has protecting effect against development of diabetic nephropathy by changing the superox‐ ide dismutase (SOD) activity, the malondialdehyde (MDA) content, and expression of Heme Oxygenase-1 (HO-1) protein.

of nitric oxide, inhibit synthesis of angiotensin 2 and TGF-β and to decelerate or prevent tu‐ bulointerstitial fibrosis in diabetic nephropathy, accompanied with control of systemic and intrarenal blood pressure. Cilostazol is a specific inhibitor of phosphodiesterase 3 (PDE 3). Its major effects are prevention of platelet aggregation and dilation of blood vessels via an increase in tissue cAMP levels (Matsumoto et al., 2005). Cilostazol was shown to inhibit vas‐ cular smooth muscle cell proliferation *in vitro* as well as suppress neointimal formation in balloon-injured rat carotid arteries due to its antiplatelet and vasodilator properties (Takaha‐ shi et al., 1992; Ishizaka et al., 1999). Our previous study showed that cilostazol decreases reactive oxygen species activity significantly in the kidneys of diabetic rats and improves urine albumin/creatinine ratio. Cilostazol also can improve the diabetes-caused increasing glomerular size, TGF-β, and NF-kB in early diabetic nephropathy (Lee et al., 2010). The lip‐ id-lowering agents such as statins, which can inhibit HMG-CoA reductase to be demonstrat‐ ed to activate eNOS, maintain glomerular filtration rate and renal cortical blood flow, and further to ameliorate glomerular lesions(Usui et al., 2003; Endres and Laufs, 2004). Benfotia‐ mine was used in the treatment of diabetic nephropathy, it was also demonstrated to reduce ROS formation and may decrease hyperfiltration and proteinuria in patients with diabetic nephropathy(Babaei-Jadidi et al., 2003). Potential therapies in these ideal antioxidants would

Antioxidants in Decelerating Diabetic Nephropathy

http://dx.doi.org/10.5772/45927

393

influence the pathways of ROS generation to decelerate diabetic nephropathy.

and Huei-Jane Lee3

1 Division of Nephrology, Department of Internal Medicine, Show Chwan Memorial Hospi‐

2 General Education Center, Central Taiwan University of Science and Technology, Tai‐

3 Institute of Biochemistry and Biotechnology, Medical College, Chung Shan Medical Uni‐

[1] American Diabetes Association(2008). Diagnosis and classification of diabetes melli‐

[2] Babaei-Jadidi, R., Karachalias, N., Ahmed, N., Battah, S., & Thornalley, P. J. (2003). Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotia‐

[3] Baldwin AS Jr(1996). The NF-KB and IKB proteins: new discoveries and insights. An‐

**Author details**

tal, Changhua, Taiwan

versity, Taichung, Taiwan

tus.Diabetes Care31: SS60., 55.

mine. *Diabetes*, 52, 2110-2120.

nu Rev Immunol, 14, 649-683.

chung, Taiwan

**References**

Wen-Chin Lee1,2\*, Chau-Jong Wang3

On the other hand, some evidences show the exogenous or endogenous antioxidants also can reduce diabetic nephropathy. Oxidative stress via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and vascular endothelial growth factor (VEGF) pathway are documented to play important roles in the development of diabetic nephropathy. Nam et al. (2009) showed the effects of apocynin, a NADPH oxidase inhibitor, on diabetic nephrop‐ athy. They found that apocynincan not significantly decrease serum glucose levels but re‐ duce urinary protein and albumin excretions. It is improved in glomerular and mesangial expansion as the apocynin treatment. Apocynin also decreased glomerular VEGF expression and reduced the concentration of 24 h urinary 8-OHdG and MDA. Additionally, Lee et al. (2005) demonstrated that antioxidant taurine prevented glomerular hypertrophy, mesangial expansion, and proteinuria in diabetic rats. Overexpression of catalytic antioxidants was al‐ so shown to protect against diabetic injury in several transgenic animals. Craven et al. (2001) showed that diabetic mice transgenic for Cu/Zn SOD had significantly lower urinary albu‐ min excretion, glomerular hypertrophy, and glomerular expression of TGF-β1 and collagen IV protein compared to non-transgenic mice. Hamada et al. (2007) demonstrated that over‐ expression a small antioxidant, thioredoxin 1, effectively inhibited 8-OHdG in the kidney, albuminuria, mesangial expansion, and tubular injury in diabetic mice. Du et al. (2003) found that overexpression of MnSOD in bovine aortic endothelial cells prevented high glu‐ cose-induced activation of PKC, NK-kB, hexosamine, and advanced glycation end product (AGE) pathways. Brezniceanu et al. (2007) demonstrated that renal catalase overexpression in db/db mice attenuated ROS generation, angiotensinogen, proapoptotic gene expression and apoptosis in the kidneys of diabetic mice *in vivo*.

Although strict glycemic control is very important in DM patients, many of the current standard therapeutic approaches may also ameliorate oxidative stress as pleiotropic effects (Singh et al., 2011), such as angiotensin-2 converting enzyme (ACE) inhibitors(Kobayashi et al., 2006), angiotensin-2 receptor blockers (ARB) (Ogawa et al., 2006) and aldosterone block‐ ers (spironolactone) (Takebayashi et al., 2006). They activate eNOS to increase bioavailability of nitric oxide, inhibit synthesis of angiotensin 2 and TGF-β and to decelerate or prevent tu‐ bulointerstitial fibrosis in diabetic nephropathy, accompanied with control of systemic and intrarenal blood pressure. Cilostazol is a specific inhibitor of phosphodiesterase 3 (PDE 3). Its major effects are prevention of platelet aggregation and dilation of blood vessels via an increase in tissue cAMP levels (Matsumoto et al., 2005). Cilostazol was shown to inhibit vas‐ cular smooth muscle cell proliferation *in vitro* as well as suppress neointimal formation in balloon-injured rat carotid arteries due to its antiplatelet and vasodilator properties (Takaha‐ shi et al., 1992; Ishizaka et al., 1999). Our previous study showed that cilostazol decreases reactive oxygen species activity significantly in the kidneys of diabetic rats and improves urine albumin/creatinine ratio. Cilostazol also can improve the diabetes-caused increasing glomerular size, TGF-β, and NF-kB in early diabetic nephropathy (Lee et al., 2010). The lip‐ id-lowering agents such as statins, which can inhibit HMG-CoA reductase to be demonstrat‐ ed to activate eNOS, maintain glomerular filtration rate and renal cortical blood flow, and further to ameliorate glomerular lesions(Usui et al., 2003; Endres and Laufs, 2004). Benfotia‐ mine was used in the treatment of diabetic nephropathy, it was also demonstrated to reduce ROS formation and may decrease hyperfiltration and proteinuria in patients with diabetic nephropathy(Babaei-Jadidi et al., 2003). Potential therapies in these ideal antioxidants would influence the pathways of ROS generation to decelerate diabetic nephropathy.
