Angiotensin II (Ang II) and transforming growth factor-beta (TGF-beta) are linked in disease states: Angiotensin II is a potent vasoactive hormone with many effects beyond blood pressure. When it is overexpressed in organ systems such as the heart, the vasculature, and the kidney, it stimulates TGF-beta production. We have available therapies to alter this axis by pharmacological blockade of the predominant Ang II receptor, AT1R, and this treatment reduces TGF-beta levels in experimental studies. However, the mechanism linking AT1R blockade and changes in TGF-beta is unknown. We propose to examine AT1R blockade and the regulation of TGF-beta in humans in a setting with an active Ang II state, chronic allograft nephropathy (CAN). The pathogenesis of CAN is certainly multifactorial. However, experimental studies have demonstrated a high level of renin-angiotensin system (RAS) activity in the kidney following transplantation, at a time when the systemic RAS is quiescent. Ang II could be functioning to maintain fluid and electrolyte homeostasis, or it could act as an immunomodulatory peptide, stimulating production of cytokines, such as TGF-beta, that lead to interstitial inflammation and fibrosis in the allograft. Published data in animal models of CAN report that AT1R blockade protects the kidney from fibrosis. However, whether this also occurs in human renal transplantation is unknown. A randomized clinical trial of patients who demonstrate early evidence of CAN has been organized, comparing treatment with Ang II receptor blockade, which is also anti-hypertensive, to other anti-hypertensive drugs that do not affect the RAS. This proposal is to assess the mechanisms of AT1R blockade in affecting TGF-beta and related signaling molecules known to participate in modulation if TGF-beta in both the transplanted renal tissue and peripheral blood. Patients 6 months or later after transplantation will be eligible if they have an increase in serum creatinine of > 0.3 mg/dl over baseline, have hypertension, and proteinuria or a biopsy showing CAN. All patients will have received a living donor graft, related or unrelated, at the University of Wisconsin. Donors and recipients will be genotyped for the AT1R A1166 --> C polymorphism, the latter being associated with a higher level of response to Ang II, and a computer program will be used to randomize in a fashion to prevent over-representation of polymorphism in one arm.
Showing the most recent 10 out of 11 publications
