myeloid MR knockouts were similar, there was a shift in the nature of macrophages such that the M2 macrophages associated with an antiinflammatory response were increased in relation to the M1 macrophages, which are proinflammatory (27). Although these studies were done in animals without diabetes, the experiments demonstrate the importance of inflammation and MRs in mediating CKD after AKI; similar mechanisms likely operate in patients with CKD resulting from diabetes (Table 1) (28,29). Innate Immunity, Complement Activation, and Diabetic Nephropathy Activation of the innate immune system through pattern recognition receptors such as membrane-bound toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors may play an important role in the pathogenesis of diabetic nephropathy (30). The complement system, in addition to fighting infections, facilitates the removal of damaged cells by antibodies and phagocytic cells. The activation of the complement component C3 generates the membrane attack complex (MAC) that lyses, damages, or activates target cells. Mannose-binding lectin (MBL) activates the lectin pathway; pattern recognition molecules called ficolins can also activate the lectin pathway. The lectin pathway is activated after binding of ficolins to glycated proteins. Glycation of complement regulatory proteins such as CD59 might by itself activate complement; this is so because CD59 normally inhibits MAC (30). A causal relation between MBL activation and diabetic nephropathy is firmly established in animals. For example, compared to wild-type mice with streptozotocin-induced diabetes, MBL knockout mice have less kidney damage, less kidney hypertrophy, lower urine albumin excretion, and less type IV collagen expression (31). Several lines of evidence in humans suggest the important role of complement activation in CKD progression. As examples, 1) in patients with type 1 diabetes, concentrations of MBL associate with progression of kidney disease from macroalbuminuria to ESRD (32); 2) in a prospective cohort study of 270 patients with newly diagnosed type 1 diabetes, H-ficolin was associated with an increased risk of worsening of albuminuria (33); and 3) MAC detected by antibodies directed against the C9 component of MAC localize it to the glomerular basement membrane (GBM), tubules, and Bowman capsule in patients with type 1 diabetes (34–36). Taken together, these data point out the important role of the complement system and its components in the pathogenesis of diabetic nephropathy. Interrelations Among Pathogenic Factors in Diabetic Nephropathy The interplay of metabolic, hemodynamic, growth, and profibrotic factors is illustrated by consideration of the following preclinical experiments (37). Cultured mesangial cells exposed to CTGF FIGURE 4 Short- and long-term effects of MRs are location dependent. In smooth muscle cells, MRs protect from short-term AKI. In contrast, MRs in myeloid cells have no short-term effects but prevent long-term inflammation and fibrosis. These experiments are helpful in understanding the long-term consequences of repeated AKI in the progression of kidney disease in diabetes. TABLE 1 MR Blockade and Kidney Protection in Diabetes ⊲ Reduced maladaptive response ⊲ Reduced ROS ⊲ Improved endothelial function ⊲ Shift in macrophage phenotype from proinflammatory (M1) to antiinflammatory (M2) ⊲ Better blood pressure control 6 CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES increase production of profibrotic molecules such as fibronectin and collagen type I (37). Although the baseline production of CTGF by mesangial cells is low, exposure of mesangial cells to increased glucose concentration (a metabolic factor) or cyclic metabolic strain (a hemodynamic factor) increases the production of CTGF (a growth factor). The induction of CTGF protein by a high glucose concentration is blocked by TGFβ1-neutralizing antibody. This suggests that another growth factor—TGFβ1—mediates the effect of high glucose concentration to provoke CTGF production. In vivo studies in obese db/db diabetic mice demonstrate that CTGF transcription was increased 28-fold after ~3.5 months of diabetes (37). At 3.5 months of diabetes, mesangial expansion was mild, and interstitial disease and proteinuria were absent. Furthermore, rather than being diffusely increased throughout the kidney, the CTGF production was limited to the glomerular compartment. These experiments demonstrate the interplay of all the pathogenic factors discussed above and underscore the complex interrelations of these factors, over time and at different locations in the kidney, in producing the histological manifestations of diabetic nephropathy. Pathological Classification of Diabetic Nephropathy According to an international consensus conference, the histological manifestations of diabetic nephropathy follow four progressive classes (Table 2) (38). The classification acknowledges lesions in the glomeruli, tubuli, and vessels, but the root of the classification system is based on the appearance of the glomerulus. According to this classification system, diabetic nephropathy progresses from thickening of the GBM, to mesangial expansion, Kimmelstiel–Wilson lesions, and global