Telmisartan Promotes the Differentiation of Monocytes Into Macrophages M2 in Diabetic Nephropathy?
Status:
Unknown status
Trial end date:
2019-07-01
Target enrollment:
Participant gender:
Summary
The severity of the diabetic nephropathy is proportional to proteinuria rate and degree of
renal interstitial fibrosis. Despite many treatments available today, diabetic nephropathy is
responsible for a quarter of cases of end-stage renal disease (ESRD) requiring the use of
renal replacement therapy or kidney transplantation. It develops as follows: chronic
hyperglycemia of diabetes abyss renal glomeruli that allow proteins in the urine room. In
response, the tubular epithelium produces monocyte chemoattractant protein-1 (MCP-1) that
attracts monocytes circulating in the renal interstitium. Monocytes then differentiate into
M1 or M2 macrophages. M1 macrophages increased MCP-1 production while M2 macrophages produce
transforming growth factor beta (TGF-β) pro-fibrogenic. Renal fibrosis is negatively
correlated with the glomerular filtration rate itself proportional to the number of nephrons.
The decrease in the number of nephrons majorises secondarily proteinuria by the onset of
focal segmental glomerulosclerosis lesions. Production of MCP-1 increases with the renal
proteinuria because M1 macrophages earning kidneys reinforce the production of MCP-1, and
fibrosis worsens because M2 macrophages infiltrate in turn kidneys and produce TGF -β.
A way of limiting renal fibrosis would be to decrease renal monocytic infiltration by
promoting the differentiation of monocytes towards macrophages M2. Although more numerous, M2
macrophages no longer benefit the kidneys because the decline of M1 macrophages decrease
renal MCP-1 production. Ex vivo IL1-β orients the differentiation of monocytes towards
macrophages M1 and IL-4 to M2. By cons in vivo, the differentiating factors are poorly known.
It is remarkable that metformin and telmisartan increase M2 macrophages M1 macrophages and
decrease, respectively, in humans and mice. Moreover, telmisartan reduces proteinuria more
than losartan in diabetic nephropathy in humans and Metformin decreases the amount of TGF-β
intra-renal mice. This effect of telmisartan is independent of the type 1 receptor of
angiotensin II (AT1R) since it is not obtained with losartan.
Telmisartan is a partial agonist of peroxisome proliferator-activated receptor gamma
(PPARgamma), the working assumption is that telmisartan fosters the transition of monocytes
to macrophages M2 form, and limit the recruitment of more monocytes in the kidneys and
therefore proteinuria and renal fibrosis. To show this, it will be compared the ability of
monocytes to differentiate ex vivo in M1 or M2 macrophages in diabetic nephropathy patients
treated with losartan or telmisartan then it will characterize the role of PPARgamma in the
monocyte / macrophage transition. Finally, it will be compared the urinary excretion of amino
terminal propeptide of procollagen type 3 (PIIINP), considered a marker of renal fibrosis in
patients receiving losartan or telmisartan.