Abstract. The current therapy for chronic proteinuric nephropathies is angiotensin-converting enzyme inhibitors (ACEi), which slow, but may not halt, the progression of disease, and which may be not effective to the same degree in all patients. In accelerated passive Heymann nephritis (PHN), this study assessed the effect of combining ACEi with angiotensin II receptor antagonist (AIIRA) and with statin that, besides lowering cholesterol, influences inflammatory and fibrogenic processes. Uninephrectomized PHN rats were divided into four groups (n ϭ 10 each) and daily given oral doses of the following: vehicle; 40 mg/L lisinopril; 100 mg/L lisinopril plus L-158,809; 0.3 mg/kg lisinopril plus L-158,809 plus cerivastatin. Treatments started at 2 mo when rats had massive proteinuria and signs of renal injury and lasted until 10 mo. Increases in BP were equally lowered by treatments. ACEi kept proteinuria at levels comparable to pretreatment and numerically lower than vehicle. The addition of AIIRA to lisinopril was more effective, being proteinuria reduced below pretreatment values and significantly lower than vehicle. When cerivastatin was added on top of ACE inhibition and AIIR blockade, urinary protein regressed to normal values and renal failure was prevented. Renal ACE activity was increased threefold in PHN, it was inhibited by more than 60% after ACEi, and decreased below control values with triple therapy. Cerivastatin inhibited ACE activity by 30%. Glomerulosclerosis, tubular damage and interstitial inflammation were ameliorated by ACEi alone or combined with AIIRA, and prevented by addition of statin. TGF-␤ 1 mRNA upregulation in PHN kidney was partially reduced after ACEi or combined with AIIRA and almost normalized after adding statin. Cerivastatin inhibited TGF-␤ 1 gene upregulation by 25%. These data suggest a possible future strategy to induce remission of proteinuria, lessen renal injury, and protect from loss of function in those patients who do not fully respond to ACEi therapy.

Esterified hyaluronic acid (HYAFF) is routinely used for clinical tissue-engineering applications such as skin and cartilage. The material is degraded by neotissue formation and degradation products are highly biocompatible. In the present article we investigate the possibility to culture vascular smooth muscle cells on this biodegradable material for the generation of tubular constructs to be used for vascular tissue engineering. We have evaluated cell attachment and growth, and the possibility to obtain a three-dimensional tubular shape culture from flat HYAFF sheets. We also evaluated the mechanical properties of the cell constructs, using a specific testing protocol, and compared them with the properties of segments of porcine coronary artery. Morphology and viability tests demonstrated that vascular cells, either from porcine or human origin, adhere and grow on nonwoven meshes of HYAFF, and that precoating of the material with fibronectin or collagen had a modest effect on cell growth and extracellular matrix production. Cell growth reached a maximum 7 days after seeding. Simple wrapping of flat sheets of nonwoven meshes containing vascular cells around a cylindrical mandrel, and culture under static conditions for 14 days, yielded tubular constructs suitable for mechanical tests. Despite cell colonization, constructs showed lower mechanical resistance as compared with porcine coronary arteries. The material used and the technique developed result in highly cellularized tubular constructs. Whether the mechanical properties may be improved by dynamic culture conditions is worthy of investigation.

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Reconstructive surgery using autologous vessels is the conventional approach for substitution of diseased vessels or for generation of bypass to improve blood supply downstream of stenosed vessels. In some circumstances the use of autologous material is not possible due to concomitant diseases or previous use, and artificial grafts must be used. Unfortunately, these grafts cannot substitute small-caliber arterial vessels because of thrombotic complications. The objective of tissue engineering at the vascular level is then to generate biological substitutes of arterial conduits with functional characteristics of native vessels, combining cellular components with biodegradable scaffolds. These research projects started in several laboratories, in the late 1990s, and have expanded in different directions using a number of experimental approaches. The objective of this review is to give an overview of the results so far obtained in this area of research, and to discuss the problems related to these investigations, at the experimental and clinical level. The article provides an overview of different biodegradable scaffolds used, experimental techniques for vessels maturation in vitro under mechanical stimulation, and of differentiated as well as precursors of vascular cells, which opens new opportunities for further development of this form of cell transplantation. Finally, the current available results in clinical research will be discussed.

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