Effect of vitamin D and matrix metalloproteinases on mesangial cell phenotype
Funding:
National Kidney Foundation of Wisconsin
Principal Investigator:
Lab Website:
(Lab website not available at this time)
Project Summary:
Chronic allograft nephropathy (CAN) is the leading cause of long-term
renal graft loss. It is characterized by the development of fibrotic changes
throughout the graft including glomerulosclerosis, interstitial fibrosis,
tubular atrophy, and concentric neointimal hyperplasia. These changes
mirror the changes that occur in many chronic renal diseases. CAN, often
termed chronic rejection (CR), is irreversible resulting in patient retransplantation
or dialysis. The etiology of CAN is unknown, but it likely involves a
complex interaction between humoral and cellular immune responses, cold
ischemic and perfusion injury, and cytokine expression, particularly TGFb-1.
Transforming growth factor beta-1 (TGFb-1) plays an important role in
the development of CAN, stimulating extracellular matrix deposition by
increasing collagen and fibronectin synthesis or by altering matrix the
expression of metalloproteinases (MMP) and tissue inhibitors of matrix
metalloproteinases (TIMP). 1,25-(OH)2D3, the active metabolite of vitamin
D, regulates immune responses in addition to its role in calcium, phosphorus,
and bone metabolism. Recent data suggests that 1,25-(OH)2D3 blocks dendritic
cell maturation influencing the development of regulatory T cells. We
have shown that high dose 1,25-(OH)2D3 monotherapy is effective at delaying
acute rejection. We and others have shown that the vitamin D receptor
(VDR), which functions as a transcription factor, forms a complex with
Smad 3, a TGFb-1 signaling protein, in rat renal lysates for treated recipients.
We have now shown that 1,25-(OH)2D3 significantly prolonged graft survival,
limited the degree of intersitial fibrosis and glomerulosclerosis, decreased
urinary protein and altered Smad and MMP expression in a rat renal model
of CAN. We have also observed, in a retrospective clinical study, that
cadaveric renal transplant recipients with renal insufficiency placed
on calcitriol demonstrate improved renal function and improved graft survival.
These results suggest that 1,25-(OH)2D3 may regulate TGFb-1-mediated ECM
deposition. Therefore, we hypothesize that 1,25-(OH)2D3 may be an effective
agent in preventing or limiting CAN. Further, we hypothesize that 1,25-(OH)2D3
may alter the balance of matrix deposition and removal in mesangial cells
by altering MMP expression.
To understand the complex cellular interaction interactions that occur
in CAN and other chronic renal diseases and in vitro model system must
be developed. Thus, in this application we propose to develop an in vitro
system to study the effects of 1,25-(OH)2D3 on masangial cell phenotype,
differentiation and ECM deposition. Primary rat masangial cells will be
isolated, placed in culture in the presence or absence of 1,25-(OH)2D3
and subjected to mechanical stretch (stress). Cellular phenotype, proliferation
and MMP and TIMP expression will be determined. To demonstrate a link
between MMP expression and the effect of 1,25-(OH)2D3, we will alter MMP
2 or MMP 9 expression in the presence or absence of 1,25-(OH)2D3 in cultured
mesangial cells subjected to stress using gene therapy.
The studies proposed in this application will allow us to begin understanding
the role of 1,25-(OH)2D3 in modifying extracellular matrix deposition
and to identify specific molecular interactions involved in the mechanism.
The results of these studies can be applied to other fibrotic renal diseases.
It is likely that the studies proposed heare will lead to new clinical
therapies.
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First published: 07/15/02 Last updated: 11/23/09
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