Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.

BACKGROUND:HMG-CoA reductase inhibitors have been shown to reduce glomerular injury in different models of progressive renal damage. The transcription factor NF-kappaB plays a major role in the induced expression of genes involved in cellular proliferation and inflammatory responses that could be important in the pathogenesis of glomerular injury. We therefore examined the effects of the HMG-CoA reductase inhibitor lovastatin on NFkappaB activation in human mesangial cells.METHODS:Cultured human mesangial cells were stimulated with bacterial lipopolysaccharide (LPS) in the presence or absence of lovastatin. NF-kappaB activity was measured by electrophoretic mobility shift assay (EMSA).RESULTS:LPS-stimulated mesangial cells exhibited an NF-kappaB-like activity as assessed by EMSA competition assays, and supershift assays with antibodies against the p50 and p65 subunits of NF-kappaB. Treatment of mesangial cells with lovstatin in the presence of exogenous cholesterol resulted in a significant reduction of the LPS-induced NF-kappaB activity. In the presence of either mevalonate or the mevalonate metabolite farnesyl pyrophosphate, the lovastatin inhibition of NF-kappaB activation was substantially reversed, supporting a role for mevalonate metabolites in LPS-induced mesangial cell NF-kappaB activation.CONCLUSIONS:These data suggest an additional mechanism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-kappaB activation and the subsequent proliferative and inflammatory responses.

Protein prenylation, the post-translational attachment of isoprenoids to certain cellular proteins, increases protein hydrophobicity and promotes protein-membrane interactions. Of the many cellular proteins that undergo protein prenylation, particular attention has been paid to the protooncogene product Ras. Prenylated Ras protein localizes to the inner cell membrane and appears to function as a "molecular switch" through which peptide growth factors such as PDGF, IGF-1, and FGF, and cytokines such as IL-2, IL-6, and GM-CSF stimulate intracellular events. Binding of these substances to their respective receptors on target cells can activate Ras, triggering intracellular signaling cascades which culminate in processes such as cell proliferation, differentiation, and T-cell activation. Protein prenylation inhibitors block Ras prenylation, prevent membrane localization of Ras, and inhibit growth and proliferation of a variety of cell types. Recent studies in our laboratory have begun to examine the possible role of Ras in chronic allograft rejection. Abdominal aorta segments from donor Lewis rats were transplanted into Buffalo recipient rats. Recipients treated with the HMG-CoA reductase inhibitor lovastatin, which inhibits isoprenoid production, showed significantly decreased allograft intimal area after 12 weeks, when compared with untreated recipients. In a separate study, recipients treated with the agent leflunomide, which inhibits growth factor receptor tyrosine kinases that can activate Ras, had significantly decreased allograft intimal area after 12 weeks. These results suggest that Ras may be important in chronic allograft rejection, and that agents that interfere with Ras protein prenylation or activation by growth factor receptors may ameliorate chronic rejection.

Increasing evidence suggests that lipids may be important modulators of progressive glomerular injury. We previously reported the long-term glomerular changes in rats with dietary-induced hypercholesterolemia. In this work, we evaluated the early glomerular changes induced by hypercholesterolemia that precede the development of glomerulosclerosis. In cholesterol-fed rats, an early macrophage influx was observed. This was associated with an increase in glomerular size, mesangial matrix expansion, lipid deposits, and foam cell formation. Immunohistochemical techniques showed that type IV collagen, fibronectin, and laminin were increased in cholesterol-fed rats. The mRNA expression for the alpha 1 chain of type IV collagen and an inhibitor of type IV collagenase were increased, suggesting that both increased synthesis and reduced degradation may be involved in cholesterol-induced mesangial matrix accumulation. The glomerular mRNA expression of transforming growth factor-beta 1 was also upregulated, suggesting that transforming growth factor-beta 1 could be an important mediator for mesangial matrix accumulation in hypercholesterolemic states. The early cholesterol-induced changes in the glomerulus are reminiscent in many respects to the process leading to glomerulosclerosis in the vessel wall.

Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. The journal celebrated its 50th year in 2016. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal.

The beneficial effects of HMG-CoA reductase inhibition in models of progressive glomerular injury may not all be due to reductions in circulating lipoproteins and decreases in glomerular lipoprotein deposition. Indeed, HMG-CoA reductase inhibitors may have direct effects on glomerular mesangial cells that could explain the amelioration of renal injury. Specifically, HMG-CoA reductase inhibitors block the synthesis of isoprenoids that are necessary for mesangial cell proliferation and other important cell functions. Thus, protein isoprenylation may play a critical role in the pathogenesis and treatment of lipid-induced glomerular injury.