**1. Introduction**

Diabetes mellitus (DM) is a group of metabolic diseases characterized with inappropriate hyperglycemia due to either a deficiency of insulin secretion or a combination of insulin re‐ sistance and inadequate insulin secretion (Masharani, 2008). Type 1 diabetes is caused by ab‐ solute deficiency of insulin secretion. Individuals at risk of developing this type of diabetes are found with serologic evidence of an autoimmune process occurring in the pancreatic is‐ lets and by genetic markers. In type 2 diabetes, it is a combination of resistance to insulin action and an inadequate compensatory insulin secretion response (American Diabetes As‐ sociation, 2008). Diabetic nephropathy, one of the common complications of diabetes, has become the leading cause of end-stage renal failure in many countries (Chen et al., 2005). In general, about 1 out of 3 patients with type 1 or type 2 diabetes proceed to developing sig‐ nificant diabetic nephropathy (Zipp and Schelling, 2003). It is believed that the pathophysio‐ logic mechanisms of renal disorder are similar in both types of diabetes (Kern et al., 1999). The pathogenesis and clinical course of diabetic nephropathy can be monitored by structural and hemodynamic changes. The earliest changes is an increase in glomerular filtration rate (GFR), also call "hyperfiltration" stage, which is followed by detectable glomerular lesions with normal albumin excretion rate. The next change is the development of microalbuminu‐ ria. Once microalbuminuria persist, both changes in glomerular structure, such as mesangial expansion and basement membrane thickening, and permeability happened, which is refer‐ red as "incipient nephropathy". Diabetic subjects with persistent microalbuminuria are at increased risk for "overt diabetic nephropathy". At this stage, prominent proteinuria, hyper‐ tension, and renal insufficiency progressed. The pathological findings in this stage are glo‐ merular basement membrane (GBM) thickening, mesangial expansion and resulting in diffuse and/or nodular glomerulosclerosis, afferent and efferent arteriolar hyalinosis, and tu‐ bulointerstitial fibrosis (Cooper and Gilbert, 2003). After several years of persistent proteinu‐ ria, progression to end-stage renal disease will occur (Caramori and Mauer, 2001).

© 2013 Lee et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advanced diabetic glomerulopathy is commonly characterized by diffuse glomerulosclero‐ sis and may sometimes exhibit a distinctive morphological appearance, namely, the nodular form of glomerulosclerosis, as first described by Kimmelstiel and Wilson in 1936 (Kimmel‐ stiel and Wilson, 1936; Kern et al., 1999). The stages of diabetic nephropathy are shown in Table 1 (Vora and Ibrahim, 2003).

β cells. Type 2 diabetes mellitus is characterized by insulin resistance and insulin secretion impairment. Animal models have been used extensively in the field of diabetes study. The current available animal models of type 1 and type 2 diabetes are shown in Table 2 (Rees

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and Alcolado, 2005).

Type 1 BB (Bio breeding) rat

Type 2 CBA/Ca mouse

Chinese hamster Celebes black ape Keeshond dog

db/db mouse Diabetic Torri rat GK (GotoKakizaki) rat Israeli sand rat KK mouse

Ob/Ob mouse

Zucker rat

**Table 2.** Animal models of type 1 and 2 diabetes mellitus

war et al., 2008; Singh et al., 2011).

LETL (Long Evans Tokushima lean) rat

New Zeland white rabbit NOD (non-obese diabetic) mouse Streptozotocin-induced rats

New Zeland obese mouse

NSY (Nagoya-Shibata-Yasuda) mouse

OLETF (Otsuka Long-Evans Tokushima fatty) rat

**3. The molecular mechanism of oxidative stress in diabetic nephropathy**

There are four major biochemical pathways considered to lead to the development of diabet‐ ic complications associated with hyperglycemia, (1) the polyol pathway, glucose is convert‐ ed to sorbitol and then metabolized to fructose. Advanced glycation end products (AGE) and reactive oxygen species (ROS) formation also occurs via this pathway, (2) the hexosa‐ mine pathway, fructose-6-phosphate is converted to glucosamine intermediates and the pro‐ duction of ROS is subsequently increased, (3) the protein kinase C (PKC) pathway, glucose is converted to glyceraldehyde-3-phosphate and leads to the formation of diacylglycerol (DAG). The elevation of intracellular DAG levels activate PKC, and then activate NADPH oxidase to induce ROS, (4) the formation of advanced glycation end products (AGEs), inter‐ action of AGEs with the receptors of advanced glycation end-products (RAGE) results in ROS activation (Stirban et al., 2008; Shah et al., 2009; Forbes et al., 2008; Brownlee, 2005; Kan‐


**Table 1.** Natural course of diabetic nephropathy in type 1 diabetes

The current strategies to treat diabetic nephropathy include intensive glycemic control, anti‐ hypertensive treatment with a particular focus on the interruption of renin-angiotensin-al‐ dosterone system (RAS), restriction of dietary protein, and treatment of hyperlipidemia. There are several new approaches to the treatment of diabetic nephropathy based on an ev‐ er-growing mechanistic understanding of the causes of diabetic nephropathy by the specific pathogenic roles. These agents include pharmacologic inhibitors of advanced glycation end products (AGEs) formation, protein kinase C (PKC), oxidative stress, and transforming growth factor β (TGF-β) (Williams and Stanton, 2005).
