activation of glucose transporting pathways in the proximal tubule early in the course of diabetes stimulates the reabsorption of both glucose and sodium in the proximal nephron (12). Sodium delivery to the distal nephron is reduced. This triggers tubuloglomerular feedback; the afferent arteriole dilates, and the efferent arteriole constricts (12). An increase in insulin by itself can increase sodium and glucose transport in the proximal tubule and provoke tubuloglomerular feedback. Insulin, as noted above, can also reduce afferent arteriolar tone directly. Thus, insulin can both directly and indirectly cause hyperfiltration. Growth Factors It has long been recognized that microangiopathy such as that occurs in the eye also associates with kidney disease. Therefore, investigators have explored the relation between vascular proliferation and endothelial permeability—factors known to be important in the pathogenesis of diabetic eye disease—with the occurrence of diabetic nephropathy. Vascular endothelial growth factor (VEGF) is activated early and leads to vascular expansion, which can provoke hyaline arteriosclerosis and hypertensive changes in the kidney (18). Similarly, angiopoietins can cause vascular proliferation and have been implicated in the pathogenesis of diabetic nephropathy (19). Proinflammatory and Profibrotic Factors Inflammation and fibrosis are important causes of diabetic nephropathy (20). Whether this is causal or in response to injury remains a matter of debate. However, there is a strong relation between the degree of infiltration of macrophages and subsequent occurrence of tubular interstitial fibrosis and progression of diabetic kidney disease (21,22). Macrophages are attracted to the kidney by a variety of mechanisms (23). Endothelial cell dysfunction, activation, and injury all stimulate the production of adhesion molecules on the endothelial surface that facilitate transendothelial migration of macrophages. Injury and activation of resident kidney cells such as podocytes, mesangial cells, and tubular cells result in secretion of chemokines that facilitate intrarenal macrophage infiltration. Macrophages are activated to the proinflammatory (M1) phenotype by ROS, angiotensin II, and the activation of mineralocorticoid receptors (MRs). That by itself can damage podocytes, endothelial cells, mesangial cells, and tubular cells. Activated macrophages, by releasing profibrotic cytokines, can increase cell proliferation and matrix volume expansion and provoke fibrosis. Fibrosis at a molecular level is mediated in part because of activation of TGFβ1, which has two synergistic effects: activation of connective tissue growth factor (CTGF) and a reduction in matrix metalloproteinases (MMPs). In contrast, MR antagonists can coax macrophages to the antiinflammatory (M2) phenotype and be protective (24). Thus, macrophages play an important role in the pathogenesis of diabetic nephropathy (23). Acute Kidney Injury, Inflammation, Chronic Kidney Disease, and the Role of MRs Inflammation and fibrosis may also be important promoters of progression of chronic kidney disease (CKD) in patients with FIGURE 3 Mechanisms of intraglomerular hypertension. Intraglomerular pressure can increase as a result of either an increase in efferent arteriolar tone or a reduction in afferent arteriolar tone. The mediators of these alterations are shown. ↑ Intraglomerular pressure ↑Efferent arteriolar tone ⊲ Angiotensin II ⊲ TxA2 ⊲ ET-1 ⊲ ROS ↓Afferent arteriolar tone ⊲ NO bioavailability ⊲ ↑COX-2 prostanoids ⊲ ↑Kallikrein-kinin system ⊲ Atrial natriuretic peptide ⊲ Angiotensin 1–7 ⊲ Insulin ⊲ Tubuloglomerular feedback CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES 5 diabetes, and this may be the result of acute kidney injury (AKI). It is increasingly being recognized that single or repeated bouts of AKI on a background of CKD in diabetes may play a vital role in the progression of CKD to ESRD (25). Macrophage infiltration is commonly seen in AKI, and depletion of macrophages in preclinical models can protect from AKI (26). In two different rodent models of AKI, bilateral ischemia reperfusion (IR) pretreatment with the nonsteroidal MR antagonist finerenone prevented the development of AKI (27). In a separate set of experiments, unilateral IR injury was also associated with reduced fibrosis when animals were pretreated with finerenone (27). Furthermore, in a pig model of IR AKI, the administration of the MR antagonist potassium canrenoate prevented the progression of AKI to CKD at 90 days (27). The relative contributions of the knockout of MRs in smooth muscle cells versus their knockout in myeloid cells have been investigated in mouse models (Figure 4) (27). With MR knockout in smooth muscle cells, IR models demonstrated that the short-term elevation of serum creatinine and blood urea nitrogen was prevented. However, at 30 days, there was no difference between wild-type and smooth muscle cell MR knockouts. In contrast to MR knockout in smooth muscle cells, among myeloid MR knockout mice, there was no immediate protection from AKI. However, at 30 days, there was a marked improvement in renal function and markers of inflammation. Furthermore, there was a shift in the polarization of macrophages infiltrating the kidney. Although the total number of macrophages in wild-type and