Background. Ischemia-reperfusion injury (IRI) is the major cause of delayed graft function in renal allografts. The present study was performed to investigate the validity of serum creatinine (SCr) level as an indicator of postischemic renal dysfunction in mice.Methods. Renal IRI or sham surgery was induced in C57BL/6 mice, and SCr level and inulin clearance (C-in) were measured between 24 hr and 7 days after ischemia.Results. C-in in IRI mice was reduced 75% at 72 hr after ischemia in association with a nearly threefold increase in SCr level. C-in in IRI mice did not recover between 72 hr and 7 days after ischemia, even though SCr level at 7 days was not different between control and IRI mice. In IRI mice, SCr level measured at 24, 48, and 72 hr after ischemia correlated inversely with C-in measured at 72 hr, but not 7 days, after ischemia.Conclusions. SCr level in the early postischemic period (24-72 hr) seems to be a valid indicator of early postischemic renal dysfunction, and that renal function remains markedly depressed at 7 days despite suggestion from the SCr value that renal function is improving.

BACKGROUND The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. METHODS Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. RESULTS Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia. CONCLUSIONS Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Hyperlipidemia is a cardinal feature of the nephrotic syndrome and is characterized primarily by increased circulating levels of cholesterol-rich and triglyceride-rich lipoproteins that contain apolipoprotein (apo) B1.Wheeler D.C. Bernard D.B. Lipid abnormalities in the nephrotic syndrome: Causes, consequences and treatment.Am J Kidney Dis. 1994; 23: 331-346Abstract Full Text PDF PubMed Scopus (151) Google Scholar. To date, most of the research has focused on the mechanism and treatment of elevated low-density lipoprotein (LDL) cholesterol associated with nephrotic syndrome because of the recognized link between elevated LDL cholesterol and atherosclerosis. Less well studied, however, are the mechanisms responsible for increased triglyceride-rich lipoproteins in the nephrotic syndrome. Elaboration of such mechanisms has potential clinical significance for at least two reasons. First, triglyceride-rich, apo B–containing lipoproteins, such as very-low-density lipoprotein (VLDL), may have atherogenic properties and increase the risk of coronary events2.Alaupovic P. Mack W.J. Knight-Gibson C. Hodis H.N. The role of triglyceride-rich lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial.Arterioscl Thromb Vasc Biol. 1997; 17: 715-722Crossref PubMed Scopus (155) Google Scholar. Second, triglyceride-rich lipoproteins may be important in the pathogenesis of renal injury and may contribute to the progression of renal disease. Indeed, Samuelsson et al have reported a strong correlation between triglyceride-rich, apo B–containing lipoproteins and the rate of progression of renal insufficiency in patients with chronic renal disease3.Samuelsson O. Mulec H. Knight-Gibson C. et al.Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency.Nephrol Dial Transplant. 1997; 12: 1908-1915Crossref PubMed Scopus (215) Google Scholar. Obese Zucker rats, an experimental model of noninsulin-dependent diabetes mellitus, have profoundly elevated triglycerides and develop progressive renal disease at a relatively young age4.Kasiske B.L. O'Donnell M.P. Cleary M.P. Keane W.F. Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats.Kidney Int. 1988; 33: 667-672Abstract Full Text PDF PubMed Scopus (406) Google Scholar. It has previously been shown that increased VLDL in patients with nephrotic syndrome is caused primarily by decreased VLDL catabolism, rather than increased VLDL synthesis5.de Sain-van der Velden M.G. Kaysen G. Barrett H.A. et al.Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis.Kidney Int. 1998; 53: 994-1001Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar. In the current issue of Kidney International, Shearer et al confirm and extend this observation in a study designed to investigate the mechanism of increased VLDL triglycerides in rats with nephrotic syndrome6.Shearer G.C. Stevenson F.T. Atkinson D.N. et al.Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome.Kidney Int. 2001; 59: 179-189Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar. A unique aspect of their study was the use of Nagase analbuminemic rats (NAR) as "controls" for the nephrotic rats. NAR are deficient in serum albumin and thus have reduced plasma oncotic pressure like nephrotic rats. By contrast, NAR have only modestly elevated triglycerides and are not proteinuric. In a well-designed series of experiments involving several complementary approaches, Shearer et al, using an in vivo kinetic analysis, initially found that elevated triglyceride levels in nephrotic rats were not the result of increased triglyceride synthesis. Importantly, these results are consistent with those found previously in nephrotic patients5.de Sain-van der Velden M.G. Kaysen G. Barrett H.A. et al.Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis.Kidney Int. 1998; 53: 994-1001Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar and provide additional evidence that increased VLDL levels in nephrotic syndrome are caused by decreased catabolism rather than increased synthesis. Moreover, these results arguably provide validation of the rat model for the study of lipoprotein alterations in the nephrotic syndrome. In the same experiment Shearer et al also found that increased triglyceride synthesis was not responsible for the modestly elevated triglycerides in NAR. At least two factors may contribute to reduced VLDL clearance in nephrotic syndrome. First, nephrotic syndrome may be associated with a reduction in lipoprotein lipase (LPL), the endothelial surface enzyme to which triglyceride-rich lipoproteins bind in order to undergo lipolysis and clearance7.Kaysen G.A. Pan X.M. Couser W.G. Staprans I. Defective lipolysis persists in hearts of rats with Heymann nephritis in the absence of nephrotic plasma.Am J Kidney Dis. 1993; 22: 128-134Abstract Full Text PDF PubMed Scopus (13) Google Scholar. Second, the triglyceride-rich VLDL particle characteristic of nephrotic syndrome may have defective binding to the endothelium. Using the Langendorff isolated perfused heart preparation, in which perfusate triglyceride levels could be controlled, Shearer et al demonstrated reduced chylomicron clearance by hearts from nephrotic rats and NAR, both of which have reduced LPL activity (chylomicrons, triglyceride-rich lipoproteins cleared by mechanisms similar to those of VLDL clearance, were isolated from normal rats and used as viable VLDL surrogates to study the rate of triglyceride lipolysis because it is much easier to radiolabel triglycerides in chylomicrons than in VLDL). Because NAR have much lower triglyceride levels than nephrotic rats, despite similarly reduced LPL activity, the results of the isolated heart experiments suggested that reduced LPL activity alone might not be sufficient to cause the markedly elevated triglyceride levels in the nephrotic rats. Thus, the authors investigated whether an alternate mechanism, that is, abnormal binding of VLDL to the endothelium, might also contribute to impaired VLDL clearance. Using rat and bovine endothelial cells cultured in the presence of controlled levels of purified LPL, the authors determined that VLDL isolated from nephrotic rats, but not from NAR, had deficient endothelial binding. It is important to recognize that optimal binding of VLDL to the endothelium appears to also require the presence of a so-called "high-affinity" form of apo E in the VLDL particle. Apo E is donated to VLDL by high-density lipoprotein (HDL), and the content of high-affinity apo E in the VLDL particle is apparently dependent on its triglyceride content8.Dergunov A.D. Smirnova E.A. Merched A. et al.Conformation of apolipoprotein E both in free and lipid-bound form may determine the avidity of triglyceride-rich lipoproteins to the LDL receptor: Structural and kinetic study.Biochim Biophys Acta. 2000; 1484: 14-28Crossref PubMed Scopus (15) Google Scholar. Triglyceride-rich VLDL, as occurs in nephrotic syndrome, may lack high-affinity apo E and thus display deficient endothelial binding. Although Shearer et al did not directly determine if VLDL of nephrotic rats was deficient in high-affinity apo E, they did demonstrate that the VLDL was triglyceride enriched, compared to VLDL from normal control rats or NAR. Moreover, they found that HDL of nephrotic rats was deficient in apo E, a potentially important new finding. In vitro endothelial binding of VLDL from nephrotic rats was substantially improved by pre-incubating the VLDL with HDL isolated from either normal, control rats, or NAR, each of which had higher apo E content than nephrotic HDL. Conversely, endothelial binding of VLDL from normal rats was impaired by pre-incubation of the VLDL with HDL from nephrotic rats. As a counterpart to the in vitro studies, infusion of HDL isolated from normal, control rats improved (although it did not normalize) chylomicron clearance in nephrotic rats. Collectively, these results suggest that abnormalities in HDL (for example, deficient apo E) may be a key factor in the reduced VLDL clearance associated with nephrotic syndrome. In addition, HDL abnormalities of the nephrotic syndrome may in some way result from proteinuria since HDL from NAR, which are not proteinuric, was not apo E–deficient and was able to correct the deficient endothelial binding of nephrotic VLDL. Given the results of the study by Shearer et al, it seems logical to direct specific therapies to correct the deficient clearance of triglyceride-rich lipoproteins in patients with nephrotic syndrome. At present, the fibrates may be useful since these agents increase lipoprotein lipase activity9.Hunninghake D.B. Pharmacologic management of triglycerides.Clin Cardiol. 1999; 22: II44-II48Google Scholar, which is deficient in nephrotic syndrome. In addition, the statins, whose main effect is to lower LDL cholesterol, can reduce triglyceride levels. In a recent study, both atorvastatin and simvastatin reduced triglyceride levels in hyperlipidemic rabbits, and simvastatin increased LPL activity by more than 70%10.Verd J.C. Peris C. Alegret M. et al.Different effect of simvastatin and atorvastatin on key enzymes involved in VLDL synthesis and catabolism in high fat/cholesterol fed rabbits.Br J Pharmacol. 1999; 127: 1479-1485Crossref PubMed Scopus (46) Google Scholar. The Simvastatin in Nephrotic Syndrome Study Group recently demonstrated the efficacy of simvastatin in reducing both LDL cholesterol and triglycerides in nephrotic patients11.Olbricht C.J. Wanner C. Thiery J. Basten A. Simvastatin in nephrotic syndrome. Simvastatin in Nephrotic Syndrome Study Group.Kidney Int. 1999; 58: S-113-S-116Google Scholar. Simvastatin and the new agent cerivastatin have been shown to increase HDL levels12.Betteridge D.J. International multicentre comparison of cerivastatin with placebo and simvastatin for the treatment of patients with primary hypercholesterolaemia. International Cerivastatin Study Group.Int J Clin Pract. 1999; 53: 243-250PubMed Google Scholar, and thus might potentially correct the HDL abnormalities that appear to play a role in the defective endothelial binding and clearance of triglyceride-rich lipoproteins in the nephrotic syndrome. Besides lipid-lowering therapy, co-treatment of patients with nephrotic syndrome with an agent such as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to reduce proteinuria also appears to be important because proteinuria, through some unknown mechanism, appears to cause HDL abnormalities that facilitate accumulation of triglyceride-rich VLDL. In conclusion, the results of the study by Shearer et al in nephrotic rats are consistent with previous clinical studies and indicate that accumulation of triglyceride-rich lipoproteins in the nephrotic syndrome results from defective clearance of these particles. Impaired clearance of triglyceride-rich VLDL may be the result of two factors: (1) reduced endothelial LPL activity, and, perhaps more important, (2) alterations in the triglyceride and apo E content of VLDL particles that impair endothelial binding and subsequent lipolysis. The results of the present study indicate that proteinuria, and not hypoalbuminemia, associated with the nephrotic syndrome appears in some way to cause reduced apo E in HDL, the particles that contribute apo E to VLDL. Therapeutic strategies to reduce triglyceride-rich lipoproteins in the nephrotic syndrome, therefore, might include agents that reduce triglycerides, elevate LPL activity, and correct HDL abnormalities.

Current investigation of the pathogenesis of tubulointerstitial injury indicates that both interstitial fibroblasts and renal tubular epithelial cells promote extracellular matrix accumulation. Moreover, two peptides--TGF-beta and angiotensin II--produced locally or delivered in the circulation, appear to play a central role in renal fibrosis. Pharmacologic amelioration of renal fibrosis may require methods directed at multiple factors involved in the fibrotic process, including angiotensin II, TGF-beta, and the proliferation and activation of interstitial fibroblasts.

Low-density lipoprotein (LDL) may contribute to the pathogenesis of glomerulosclerosis by stimulating a mesangial cell inflammatory response. Interleukin-6 (IL-6) is a marker of active inflammation and ongoing glomerular injury. Therefore, we investigated the effects of native and oxidized LDL on human mesangial cell production of IL-6 and a possible modulation of this inflammatory response by lovastatin, which has been shown to ameliorate experimental glomerulosclerosis. Human mesangial cells were exposed for 6 or 24 h to culture medium containing either native LDL alone or a LDL mixture containing 5 or 20% oxidized LDL. We found that native LDL stimulated 6 h mRNA expression and secretion of IL-6. This effect was further enhanced, in a dose-related manner, when mesangial cells were exposed to increasing concentrations of oxidized LDL. Lovastatin markedly inhibited mesangial cell expression of IL-6 mRNA and reduced IL-6 secretion. The inhibitory effects of lovastatin were overridden at least partially by exogenous mevalonate. We conclude that LDL, and particularly oxidized LDL, might contribute to the pathogenesis of glomerular disease by modulating the inflammatory response of human mesangial cells, as assessed by the stimulation of IL-6 expression. Moreover, this inflammatory response can be prevented by lovastatin, providing a potential direct anti-inflammatory mechanism by which HMG-CoA reductase inhibitors may attenuate lipid-induced glomerular injury.

Background. The sequential appearance of cyclins D and E is thought to initiate subsequent DNA synthesis in proliferating cells. Previous studies have reported that DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs) was suppressed by the HMG-CoA reductase inhibitor lovastatin. The effects of lovastatin on cell cycle regulatory proteins in proliferating VSMCs, however, are largely unknown. Thus, we investigated the sequential expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 4, CDK2, and p27Kip1 in cultured rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB in the presence or absence of lovastatin.Methods. Quiescent VSMCs, with and without lovastatin (20 mu M) pretreatment for nine hours, were stimulated by PDGF-BB (25 ng/ml). The incorporation of tritiated thymidine was done to assess DNA synthesis. VSMC lysates were obtained every 6 hours for up to 36 hours after stimulation and were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis using relevant polyclonal antibodies. Autoradiograms were analyzed using a densitometer.Results. The peak expression of cyclins D1 and E occurred at 18 and 30 hours of PDGF stimulation, respectively. Concomitant expression of CDK4 and CDK2 was also observed. The expression of p27Kip1. by contrast, was reduced in association with DNA synthesis. Lovastatin suppressed DNA synthesis and reduced the expression of cyclin D1 and cyclin E, whereas p27Kip1 expression was strongly induced by lovastatin pretreatment. CDK4 and CDK2 expression was unaffected by lovastatin treatment.Conclusions. PDGF-BB induces cyclins D1 and E prior to the onset of DNA synthesis in VSMCs. Lovastatin may suppress DNA synthesis in VSMCs by inducing p27Kip1 and reducing expression of cyclins D1 and E.

Background Farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP) are isoprenoid products of the intracellular mevalonate pathway used for prenylation of several low molecular weight G proteins, including Ras. It is likely that platelet-derived growth factor (PDGF) stimulation of mesangial cell proliferation requires prenylated, low molecular weight G proteins. The purpose of this study was to investigate the dependence of platelet-derived growth factor-stimulated mesangial cell DNA synthesis and cell membrane Ras incorporation on FPP and GGPP.Methods. Quiescent human mesangial cells were exposed to PDGF (25 ng/ml) to stimulate DNA synthesis. Some cells were also treated with the HMG-CoA reductase inhibitor lovastatin (2.5 to 10.0 mu M), which inhibits isoprenoid synthesis, in the presence or absence of exogenous FPP or GGPP. DNA synthesis was assessed by thymidine incorporation. and Western blot analysis was used to measure total cell membrane Ras.Results. Stimulation of mesangial cells with PDGF did not increase total cell membrane Ras. Lovastatin reduced cell membrane Ras, and this was prevented by simultaneous exposure of mesangial cells to exogenous FPP (2.5 to 10.0 mu M) or GGPP (1 to 5 mu M). Lovastatin also reduced PDGF-stimulated mesangial cell DNA synthesis by 90%, and this was completely prevented by simultaneous exposure of cells to exogenous GGPP (1 mu M). but not to FPP.Conclusions. The results of this study suggest that both FPP and GGPP can provide for mesangial cell membrane Ras localization and that PDGF-stimulated mesangial cell DNA synthesis requires the isoprenoid GGPP.

Background. The accumulation of vascular smooth muscle cells (VSMC) in the intima is an early feature of atherosclerosis that results from a balance of migration from the media, proliferation, an eventual death (including programmed cell death) of VSMC. Several reports have described that HMG-CoA reductase inhibitors (statins) attenuate both the migration and proliferation of VSMC. However, the potential effect of statins on VSMC programmed cell death has received little attention.Methods. Human and rat VSMC were incubated with different concentration of statins in the presence of fetal bovine serum as a survival factor. The presence of apoptosis was evaluated by morphological criteria, Bow cytometry and DNA electrophoresis.Results. Lipophilic statins induced, in a dose-dependent manner the appearance of VSMC apoptosis. The effect of statins was fully reversed by mevalonate, farnesylpyrophosphate. and geranylgeranypyrophosphate, but not by cholesterol or other mevalonate metabolites, suggesting a role for isoprenoids in VSMC apoptosis. In addition, the induction of apoptosis by statins was associated with the inhibition of prenylation of Rho B.Conclusions. The present results suggest that protein prenylation inhibition by statins may be involved in statin-induced VSMC apoptosis, These data provide a new potential mechanism by which statins may modulate the evolution of atherosclerotic lesions.

Background. Nuclear factor-kappa B (NF-kappa B) is a family of transcription factors that is recognized by the kappa B enhancer element. Numerous proinflammatory genes have binding sites for NF-kappa B, and the products of these genes are an integral part of cellular activation and inflammatory response systems. Because there is a close relationship between NF-kappa B and mediators of cell activation, it is possible that a disruption of NF-kappa B-activating pathways may effectively influence mesangial cell activationMethods, We reviewed available studies related to both NF-kappa B and mesangial cells in order to provide evidence for the role of NF-kappa B in mesangial cell activation.Results. Studies reported by this laboratory and others showed that various experimental maneuvers that modulate NF-kappa B activation result in a parallel modulation of proinflammatory molecule production in cultured mesangial cells. Likewise, the ability of the inhibitors of NF-kappa B activation to downregulate the inflammatory response in animal models of renal disease has been recently demonstrated.Conclusions. These data suggest a pivotal role of NF-kappa B in mesangial cell activation and designate it as an obvious target for the modulation of this activation. Studies are necessary to characterize the role of NF-kappa B in human renal injury.

Renal infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes might play an important role in the development of HIV-associated nephropathy (HIVAN). In the present study, we investigated the effects of cytokines produced by cultured human mesangial cells (HMC) and proximal tubular epithelial cells (PTEC) on HIV-1 expression in chronically HIV-1-infected promonocytes (U1 cells). Human mesangial cells constitutively secreted interleukin-6 (IL-6) but not tumor necrosis factor-alpha (TNF-alpha) into the culture medium, whereas PTEC constitutively secreted both IL-6 and TNF-alpha. Coculture of U1 cells with HMC or PTEC for 72 hours markedly stimulated HIV-1 expression, with the p24 antigen concentration in the coculture supernatants ranging from approximately 200 to 1850 pg/ml. The presence of anti-IL-6 antibody in the coculture medium nearly completely blocked HIV-1 expression in the HMC/U1 cell cocultures (P < 0.05). Anti-IL-6 antibody and anti-TNF-alpha antibody blocked HIV-1 expression in the PTEC/U1 cell cocultures by 40% and 53%, respectively (P < 0.05). Moreover, the combination of anti-IL-6 and anti-TNF-alpha antibodies additively reduced coculture HIV-1 expression by 87% (P < 0.05). We conclude that renal cell production of IL-6 and TNF-alpha might provide a potent stimulus for HIV-1 expression in HIV-1-infected monocytes that infiltrate the kidney, and that this may play an important role in the pathogenesis of HIVAN.

Glomerular expression of monocyte chemoattractant protein-1 (MCP-1) and subsequent glomerular macrophage infiltration may play an important role in the development of glomerulosclerosis. Previous studies have shown that lovastatin ameliorates experimental renal disease and reduces MCP-1 expression in serum-stimulated, cultured mesangial cells. We investigated the effects of lovastatin on glomerular MCP-1 expression and macrophage infiltration in rats with puromycin aminonucleoside (PA) nephrosis, an experimental model of renal disease characterized by early macrophage infiltration. Male Sprague-Dawley rats were pretreated for 5 days with either lovastatin (4 mg/kg) or vehicle. At the end of pretreatment, the lovastatin-pretreated rats received a single i.v. injection of PA (50 mg/kg) and continued to receive daily lovastatin thereafter. The vehicle-pretreated rats received i.v. injections of either PA or saline, and continued to receive daily vehicle treatment thereafter. Ten days after PA injection, the vehicle-treated PA rats showed increased (P < 0.05) serum cholesterol (359 +/- 25 mg/100 mL) and urine albumin excretion (343 +/- 95 mg/24 hr), compared with the vehicle-treated control rats (61 +/- 3 mg/100 mL and 2.5 +/- 0.6 mg/24 hr, respectively). Serum cholesterol (193 +/- 22 mg/dL) and urine albumin excretion (255 +/- 68 mg/24 hr) were less in the lovastatin-treated PA rats than in the vehicle-treated PA rats. The number of glomerular macrophages, assessed as ED-1-positive cells, per glomerular profile was increased 77% in the vehicle-treated PA rats (3.3 +/- 0.2) compared with the vehicle-treated control rats (1.8 +/- 0.2) (P < 0.05). By contrast, the number of glomerular macrophages was not elevated in the lovastatin-treated PA rats (2.3 +/- 0.2). Thus, lovastatin in vivo can attenuate glomerular macrophage infiltration. This may represent one mechanism by which lovastatin ameliorates experimental glomerular disease. (Am J Kidney Dis 1998 Jan;31(1):190-4)

In the present study, we investigated the effects of the angiotensin (Ang) II receptor antagonist, irbesartan, on blood pressure and renal structural injury in obese Zucker rats (OZR), an experimental model of non-insulin-dependent diabetes mellitus (NIDDM). Twenty-six-week-old OZR with established renal disease were administered either low-dose (15 mg/kg) or high-dose (50 mg/kg) irbesartan in the drinking water for a period of 18 weeks. Irbesartan caused dose-related reductions in blood pressure, and reduced by 47 to 60% the percent of glomeruli with sclerosis at 44 weeks of age (P < 0.05). In addition, irbesartan at the higher dose reduced the tubulointerstitial injury score at 44 weeks by approximately 75% (P < 0.05). By contrast, irbesartan did not significantly reduce albuminuria in OZR. The results of the present study demonstrate that the Ang II receptor antagonist irbesartan can reduce blood pressure and ameliorate glomerular and tubulointerstitial injury in an experimental model of NIDDM.

Products of intracellular mevalonate metabolism are critical for the growth and proliferation of eukaryotic cells. These products include cholesterol and several nonsterol isoprenoids. The isoprenoid farnesyl is a particularly important intermediate in the mevalonate pathway. Farnesyl can be used to synthesize cholesterol and can also bind covalently to several low molecular mass GTP-binding proteins such as p21 ras. Farnesylated p21 ras may be critical for mitogenic signalling stimulated by growth factors such as platelet-derived growth factor. Inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, such as lovastatin and compactin, block the production of mevalonate and its metabolites. These agents have been shown to inhibit proliferation of many cell types. Recently we demonstrated that lovastatin inhibited proliferation of cultured glomerular mesangial cells. Lovastatin inhibition was overcome by the simultaneous addition of either mevalonate or farnesol, but not by exogenous low density lipoprotein cholesterol. These results suggested that farnesyl is critical for mesangial cell proliferation. In several experimental models of renal disease, chronic lovastatin administration reduced the extent of glomerular injury. The beneficial effects of lovastatin have been attributed to lowering of circulating lipid and lipoprotein levels. In view of recent data, however, it is possible that lovastatin may act to reduce glomerular injury, at least in part, through a direct action on mesangial cell proliferation.

Experiments in animal models suggest that correcting abnormalities in lipid metabolism could help slow the rate of functional decline in patients with chronic progressive renal disease. Circumstantial evidence in humans also suggests that lipids may play a role in the pathogenesis of glomerulosclerosis. Nevertheless, large controlled clinical trials examining the effect of lipid-lowering strategies on renal disease progression have not been carried out. However, the recent development of antilipemic agents that appear to be safe and effective in patients with renal disease should make it possible to determine whether treating hyperlipidemia will reduce the rate of renal disease progression.

Altogether, a growing amount of clinical and experimental data suggests that lipids may be important in the development and progression of chronic renal injury. Abundant clinical data have demonstrated that hyperlipidemia is associated with diabetes, decreased renal function, and the nephrotic syndrome. Although clinical correlations between plasma lipid levels and renal dysfunction do not prove a cause-and-effect relationship, potentially injurious lipid abnormalities are invariably present in those patients most likely to progress to end-stage renal disease. In several animal models, pharmacologic treatment of lipid abnormalities has been shown to ameliorate renal disease. Moreover, experimental data suggest that lipid-induced alterations in a number of immune and nonimmune mechanisms could explain the association between lipids and renal injury. A better understanding of these alterations and mechanisms may ultimately lead to more effective treatment of patients with chronic progressive renal disease.

Focal glomerulosclerosis (FGS) is commonly seen in human and in experimental models of chronic renal disease. Although considerable experimental data suggest that hypertension is important in progressive nephron damage, recent studies also have indicated that abnormal lipid metabolism may be an independent risk factor in the pathogenesis of FGS. Indeed, the synergistic impact of hypertension and hyperlipidemia in the pathogenesis of FGS may be analogous to the role of these factors in the pathogenesis of atherosclerosis. This review focuses on some of the recent and pertinent data that support a role of lipid-mediated glomerular injury in the pathogenesis of progressive renal disease.

Progressive deterioration in renal function frequently occurs in the absence of the original cause of injury. During the past decade, intense investigations into the factors responsible for progressive nephron destruction have demonstrated that hemodynamic stresses and metabolic and coagulation abnormalities participate in glomerular injury. Hyperlipidemia is a common abnormality in renal disease and is frequently aggravated by protein-uria. Experimentally, therapy with the lipid-lowering agents clofibric acid or lovastatin reduced circulating lipids, particularly cholesterol, decreased proteinuria, and prevented glomerular damage in normotensive and hypertensive models of progressive renal disease. These beneficial effects occurred independently of changes in systemic blood pressure or glomerular injury, supporting the notion that cholesterol or its accompanying changes, or both, were central in lipid modulation of glomerulosclerosis. Clinically, lipid abnormalities are common in patients with renal disease, and atherosclerotic cardiovascular disease is the most frequent cause of death in these patients. Although the role of lipids in atherosclerotic disease has been well established, whether a similar effect of lipids occurs in the microvasculature of the kidney is unknown. Whether therapeutic approaches directed at reducing hyperlipidemia in patients with renal disease will provide a measure of renal protection, as has been seen in experimental models of renal disease, is also unknown.

Systemic and glomerular hypertension, hyperlipidemia, and massive proteinuria have been described as risk factors for the development of focal glomerulosclerosis (FGS). Previous studies have shown that Dahl salt-sensitive (S) rats with severe hypertension have elevated glomerular pressures and develop extensive FGS. In the present study, we determined whether Dahl S rats exhibit other risk factors for FGS. Dahl S rats were found to have elevated serum triglycerides at six weeks of age, compared to Dahl salt-resistant (R) rats. Between six and 24 weeks, systemic hypertension and progressive increases in both serum lipids and albuminuria occurred in Dahl S rats fed high salt (4% NaCl) chow. No changes in blood pressure or serum lipids occurred in Dahl R rats fed high salt. At 30 weeks, the incidence of FGS was 20 times greater in hypertensive Dahl S than in Dahl R. In a separate study, we compared risk factors for FGS in Dahl S rats and spontaneously hypertensive rats (SHR). The magnitude of glomerular capillary pressure, serum lipid levels, and urine albumin excretion were measured in male Dahl S rats and male SHR between 12 and 20 weeks of age. Normal values for the various parameters were established in a group of normotensive male Sprague-Dawley rats. For this study, all rats were fed standard chow containing 0.6% NaCl. Blood pressure was elevated (P less than .01) in Dahl S (142 +/- 2 mm Hg) and in SHR (173 +/- 3 mm Hg) compared to the Sprague-Dawley rats (117 +/- 3 mm Hg). Glomerular capillary pressure, however, was similar in all three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of lipids in the pathogenesis of focal glomerulosclerosis (FGS) was evaluated using two chemically different lipid lowering agents, clofibric acid and mevinolin. Pharmacologically, these two agents have different mechanisms of action. Clofibric acid affects both cholesterol and triglyceride metabolism, while mevinolin inhibits 3-hydroxy-3 methyl-glutaryl coenzyme A reductase, the rate limiting enzyme in cellular cholesterol synthesis. In two different models of FGS in which hyperlipidemia occurs, the obese Zucker rat and the 5/6 nephrectomy model, both agents significantly reduced FGS and albuminuria. Since glomerular hemodynamic function is normal in obese Zucker rats, these results suggested that lipids are an independent factor in the pathogenesis of FGS. Moreover, in the 5/6 nephrectomy model, the beneficial effects on glomerular structure of reducing serum lipids occurred despite persistent systemic and glomerular hypertension. Thus, we postulated that a synergistic interaction between lipids and hypertension might exist in the pathogenesis of FGS.