Abstract
Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin–angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.
Highlights
Sustained fasting glycemia over 7.00 mmol/L is the definition of diabetes mellitus that may result either from insulin deficiency following insulin resistance in type 2 diabetes (T2D) or from insulin deficiency caused by destruction of beta cells in the pancreatic islets in type 1 diabetes (T1D)
With regard to intrarenal overproduction of aldosterone in the urine, which is not lowered by enalapril in db/db mice [146], this paradoxical phenomenon may be due to the stimulation of the mineralocorticoid receptor (MR) on macrophages. In line with this interpretation, albuminuria is suppressed at week 6 and not any longer at week 12 [144], suggesting that aldosterone might increase albuminuria [147] despite ACE inhibition. These studies demonstrate that beneficial effects of Angiotensin-converting enzyme inhibitors (ACEI) or Angiotensin receptor blockers (ARB) on renal function, albuminuria and fibrosis are associated with a decreased macrophage count intrinsic to the kidneys (Figure 2)
The renin–angiotensin system (RAS) intrinsic to the kidneys and monocyte/macrophage interactions may worsen the lesions of Diabetic nephropathy (DN)
Summary
Sustained fasting glycemia over 7.00 mmol/L is the definition of diabetes mellitus that may result either from insulin deficiency following insulin resistance in type 2 diabetes (T2D) or from insulin deficiency caused by destruction of beta cells in the pancreatic islets in type 1 diabetes (T1D). Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the world and is considered an inflammatory disease. This is illustrated by renal infiltration of monocytes originating from the bone marrow and by lower occurrence of kidney lesions observed in experimental studies targeting disruption of monocytes/macrophages [1]. RAS intrinsic to the kidneys [5,6] and some components of the RAS intrinsic to the monocyte/macrophage system [7,8]. Blockade of the activated harmful RAS components in humans decreases blood pressure and albuminuria and improves the trajectory of the renal function [11]. We review the interactions of the kidneys and the monocyte/macrophage system through the RAS in DN in order to highlight the potential treatments available
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