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ACE Inhibitors Improve Diabetic Nephropathy by Suppressing Renal MCP-1


ACE Inhibitors Improve Diabetic Nephropathy by Suppressing Renal  MCP-1

The complete or almost complete failure of the kidneys to function is a condition called end-stage kidney (renal) disease. In this case, the kidneys can no longer remove wastes, concentrate urine, and regulate many other important body functions.

Diabetic nephropathy is kidney disease or damage that results as a complication of diabetes. The single most important reason for end-stage renal disease in the western world is becoming diabetic nephropathy due to type 2 diabetes. Aseptic tubulitis and tubulointerstitial fibrosis are some of the characteristics of diabetic nephropathy, in addition to glomerular damage and glomerulosclerosis. Macrophages and macrophage products have been implicated as effector cells of tubulointerstitial damage in diabetic nephropathy, and they play an important pathogenic role in tubulointerstitial inflammatory and noninflammatory conditions.

 

In biopsies of patients with diabetic nephropathy and in rat models of experimental diabetes, increased numbers of glomerular and interstitial macrophages have been observed. Monocytes are attracted to the place of organ damage by monocytespecific chemokines. Monocytes transmigrate from the vascular bed into the tissue at the point of the hightest chemokine concentration, and follow an endothelial-bound gradient of chemokine molecules. Consequently, the local generation of chemokines is not reflected by its systemic levels. The anatomical compartment where chemokines are produced or in the near vicinity thereof is the only way to do a meaningful determination of chemokine expression. This is either the kidney itself or urine in renal diseases.

 

The strongest known chemotactic factor for monocytes is monocyte chemoattractant protein-1 (MCP-1), which is upregulated in many renal diseases, including diabetic nephropathy. Renal MCP-1 expression is induced by tubular reabsorbed protein, elevated glucose levels, and probably advanced glycosylated end products. The tissue reninangiotensin system (RAS) of the kidneys is activated in diabetes. Studies that where conducted on type 1 and type 2 diabetes demonstrated that abrogation of angiotensin (AT)-II activity either with ACE inhibitors (ACEIs) or AT-II type 1a receptor antagonists slowed the loss of renal function more effectively than treatment with other antihypertensive drugs even in the absence of systemic hypertention.

The nephroprotecive effect of ACEIs is due to inhibition of the RAS but not due to other ACE-mediated processes, which this was shown in additional evidence from experiments with specific AT-1a receptor antagonists.

 

It has been shown recently that AT-II directly induces the expression of MCP-1 in vascular smooth muscle cells, in addition to the systemic and renal hemodynamic effect of AT-II. Additionally, AT-II in experimental nephritis activates the transcription factor nuclear factor-kB and initiates MCP-1 synthesis in renal cells with subsequent interstitial recruitment of monocytes and interstitial fibrosis; ACE inhibition could block this effect.

 

The tubular epithelial cells are the main renal source of MCP-1, thus, the renal production of MCP-1 may be reduced by blockade of the RAS, subsequently, the resulting decrease in monocyte immigration and monocyte activity would ameliorate interstitial fibrosis and, thus, stabilize or improve renal function. The relationship between urinary MCP-1 (uMCP-1) and renal function was investigated in patients with type 2 diabetes and diabetic nephropathy, in order to test this hypothesis.

 

uMCP-1 reflects the renal production of this chemokine in the absence of urinary tract infection. So uMCP-1 was measured before and after 1 year of treatment with the ACEI lisinopril.

 

Conclusions:

In patients with diabetic nephropathy who were treated with the ACEI lisinopril, a drastic reduction of urinary levels of the chemokine MCP-1 was described. Additionally, the improvement that was observed in proteinuria correlated well with the reduction of MCP-1 levels, and there was no correlation between uMCP-1 and glycemic control, blood pressure, or serum lipid levels.

 

The findings in an animal model of diabetic nephropathy are consistent with these results. Treatment with ACEI in rats with streptozotocininduced diabetes specifically improved renal function without affecting the levels of other fibrogenic chemokines, and decreased renal MCP-1 mRNA. Improvement of proteinuria in this animal model correlated closely with the reduction in renal MCP-1 mRNA. In the animal treated with ACEI or AT-II type 1a receptor antagonists, glomerular and tubulointertitial monocyte/macrophage infiltration was significantly reduced.

ACE-I therapy

Figure 1 – Change of uMCP-1 levels in individual patients before and after one year of ACEI therapy.

 

For the progression of diabetic nephropathy, the extent of tubulointerstitial lesions is a prognostic factor. Increased intrarenal production of MCP-1 may be a pathogenic pathway also in human diabetic nephropathy, which was shown in the study. The connection between AT-II and MCP-1 in diabetic nephropathy is not completely understood, even though higher urinary levels of MCP-1 have been detected in patients with diabetic nephropathy in the macro- than in the microalbuminuric range. It's thought that predominantly nonhemodynamic actions of AT-II are responsible for the observed decrease in uMCP-1 and the accompanying improvement of renal function.

ACE-I therapy 2

Figure 2 - Change in proteinuria in individual patients before and after 1 year of ACEI therapy.

 

In the cases of chronic renal diseases without systemic hypertension, blockade of the AT-II type 1a receptor or treatment with ACE-I is effective in reducing proteinuria.

 

Recently, there has been focus of the importance of nonhemodynamic mechanisms of AT-II in diabetic nephropathy. AT-II is a direct stimulus of MCP-1 in the mesanial cells of the kidney and in vascular smooth muscle. AT-II itself has monocyte chemoattractant activity, and activated macrophages themselves, and in addition to being potent sources of MCP-1, it can generate AT-II via an intrinsic ACE pathway. Influx of macrophages into the kidney, which can be attenuated by the administration of an AT1a-receptor antagonist, can be the result of the infusion of AT-II into rats. Less interstitial fibrosis and preserved renal function in mouse model of anti-Gbm nephritis were markedly the result of diminished expression of MCP-1, in experiments with AT-1a-receptor– deficient mice. The characteristic histological features of diabetic nephropathy in man include extracellular matrix accumulation, fibrosis of the kidney interstitium, and interstitial monocyte infiltration. Monocytes move along a concentration gradient to the place with highest expression of MCP-1, which in the kidneys are the proximal tubular cells. Proliferation and transformation of dormant fibrocytes to myofibroblasts, and the interstitial scarring and tubular atrophy that ensues is induced by activated monocytes/macrophages.

 

Protein overload of proximal tubular epithelial cells can be caused by increased glomerular capillary pressure and subsequently increased protein filtration. Tubular cells can secrete MCP-1 into the tubulus and in the adjacent interstitium in response to protein overload. The amount of protein in the tubular fluid may be theoretically diminished, and MCP-1 secretion would subsequently decrease because of amelioration of glomerular capillary hypertension via blockade of the RAS.

 

As the impressive reduction of uMCP-1 levels in all patients and not only in those with frank proteinuria, it is thought that this mechanism is probably only functional in patients with a daily protein excretion in the nephrotic range.

 

Treatment with statins for hyperlipidemia was initiated concomitantly with ACEI therapy in eight patients in this study, and since the treatment with lovastatin and atorvastatin showed a reduction in MCP-1 expression in glomerular cells and vascular smooth muscle cells, respectively, the reduction in cholesterol levels in statin-treated patients was correlated with uMCP-1, but uMCP-1 levels was not influenced by changes in cholesterol levels.

 

Blockade of AT-II with ACEI may exert its beneficial effects on renal function in patients with type 2 diabetes and diabetic nephropathy, via suppression of the AT-II- induced tubular production of the chemokine MCP-1. Decrease in the number and the activity of interstitial monocytes might be the result of this. The progression of tubulointerstitial fibrosis and tubular atrophy might be subsequently slowed.

 

The clarification of the findings in this study is consistent with the theory that AT-II/MCP-1–induced renal fibrosis is an important part of diabetic nephropathy as well as of other noninflammatory renal disease. To clarify this issue more, long-term studies concerning the role of MCP-1 and of its specific pharmacological suppression in diabetic nephropathy are needed.

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Prepared By: Dr. Mehyar Al-khashroum
Edited By: Miss Araz Kahvedjian




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