Impact of dietary fatty acid supplementation on renal injury in obese Zucker rats

We previously reported that renal injury in hyperlipidemic, obese Zucker rats was associated with a relative deficiency of tissue polyunsaturated fatty acids (PUFA). In the present study 10-week-old obese Zucker rats were pair fed regular chow or chow containing either 20% sunflower oil rich in n-6 PUFA, fish oil rich in n-3 PUFA, coconut oil medium-chain saturated fatty acid, or beef tallow long-chain saturated fatty acid. At 34 weeks of age there were comparable reductions in albuminuria, mesangial matrix expansion, and glomerulosclerosis in the fish oil and sunflower oil groups. While both fish oil and sunflower oil reduced serum triglycerides, and improved the composition of triglyceride-enriched lipoproteins, only fish oil decreased serum cholesterol. The effect of the dietary fatty acid supplementation on fatty acid profiles were similar in isolated glomeruli and cortical tissue. In general, the amelioration in injury in the fish oil and sunflower oil fed rats was most closely linked to glomerular levels of PUFA, either n-6 or n-3. These data suggest that hyperlipidemia and abnormalities in tissue FA are closely linked, and that dietary supplementation with PUFA may ameliorate chronic, progressive renal injury.     

High linoleic acid diets ameliorate diabetic nephropathy in rats

The value of high polyunsaturated fatty acid (PUFA) diets in preventing diabetic nephropathy in rats was studied. Diabetes was induced by intravenous injection of streptozotocin (SZ), 65 mg/kg. Rats were divided in four groups fed diets containing 11% fat for 38 weeks. Dietary fat derived from four sources: beef tallow (BT; rich in saturated fatty acids), evening primrose oil (EPO; rich in gamma linolenic [GLA] and linoleic acids [LA]), safflower oil (SO; rich in LA), and fish oil (FO; rich in eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids). Ultralente insulin was administered every other day to maintain the blood glucose levels between 11.1 and 22.2 mmol/L (200 and 400 mg/dL). The diets prepared with EPO and SO had a clear beneficial effect on proteinuria, glomerular sclerosis, and tubular abnormalities, as compared with BT. Both diets also increased the ratio of renal cortical production of 6-keto-PGF1 alpha to thromboxane B2 (TXB2), the stable metabolites of PGI2 and TXA2, respectively. They did not induce significant changes in plasma lipid composition. The FO diet did not have an effect on renal disease, but decreased plasma lipids and inhibited eicosanoid synthesis by platelets and kidney cortex. FO feeding was associated with a lowered 6-keto-PGF1 alpha/TXB2 ratio. It is concluded that high LA diets are protective in this model of diabetic nephropathy. The effect may be secondary to modifications of the eicosanoid balance. Diets containing FO have a beneficial effect on plasma lipids in this model.     

Effects of dietary fish oil on renal insufficiency in rats with subtotal nephrectomy

We studied the effects of fish oil on the progression of renal insufficiency in rats with subtotal nephrectomy. Five weeks after a 1-2/3 nephrectomy, sixteen rats were fed two different diets which differed only in fat composition. Lipid in the control diet was primarily beef tallow; that of the experimental diet, menhaden oil. Fish oil-fed rats had significant increases in plasma creatinines, decreases in urinary PGE2 and accelerated death rates. An additional twelve rats underwent 1-1/3 nephrectomies, and the same dietary manipulations, followed by renal clearance, histologic and biochemical studies after 12 weeks on the diets. Fish oil-fed rats again did worse, with decreased glomerular filtration rates and filtration fractions, more proteinuria and more glomerular sclerosis. Glomeruli and slices of cortex, medulla and papillae from rats fed fish oil produced much less PGE2 and TXB2 than dietary controls. Fish oil-induced suppression of renal PGE2 may be deleterious in this model and may outweigh the beneficial effect derived from TXA2 suppression. In contrast to fish oil's potentially therapeutic role in cardiovascular and immune-mediated renal disease, this diet is detrimental in rat renoprival nephropathy. This illustrates the importance of examining the effects of fatty acid manipulation individually for each disease entity.     

Effects of dietary fish oil on renal growth and function in uninephrectomized rats

The basic mechanisms of renal growth remain poorly understood. The work hypertrophy theory holds that after an acute reduction in renal mass, the growth of the kidney occurs as a consequence of increased renal function. Pharmacological inhibition of renal prostaglandin synthesis impairs the acute adaptive increases in both renal function and mass following partial nephrectomy. The present study examines the effects of four weeks of dietary fish oil on renal growth, function and arachidonic acid metabolites in intact and uninephrectomized male Sprague-Dawley rats. Dietary fish oil interferes with dienoic prostaglandin and thromboxane production in favor of synthesis of trienoic analogues. Control animals were pair-fed an identical diet with the exception that the fat was replaced by beef tallow. Renal cortical concentrations of arachidonic acid metabolites were reduced in animals fed fish oil, and urinary excretion of prostaglandin E2 was impaired. Fish oil feeding resulted in increased kidney weight without concomitant increases in renal function in intact animals. Glomerular filtration rate and renal plasma flow were greater in uninephrectomized rats fed fish oil compared to uninephrectomized controls pair-fed beef tallow. Augmentation of the compensatory increases in renal function observed with fish oil feeding was not associated with any additional renal hypertrophy. These data indicate that dietary fish oil has a profound impact on renal growth and function, which may be the consequence of altered renal and/or extrarenal arachidonic acid metabolism. Furthermore, the direction of the alterations in renal mass oppose that of renal function, providing clear and unique evidence against the work hypertrophy theory of renal growth.     

Effect of dietary fish oil on plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha levels in septic rats

Increased mortality from sepsis is associated with high levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha). Linoleic acid, an n-6 essential fatty acid, is the usual precursor of TXB2 and PGF1 alpha, while fish oil is rich in n-3 essential fatty acid, the precursor of less active moieties. Rats were fed chow, an essential fatty acid-deficient diet, or an essential fatty acid-deficient diet supplemented with linoleic acid or fish oil for 2 weeks. The animals then underwent a sham operation or cecal ligation and puncture to induce sepsis. Six hours later, blood was obtained for analysis. The chow and linoleic acid diets produced significant (twofold to fivefold) increases in levels of both TXB2 and PGF1 alpha after sepsis. The essential fatty acid-deficient diet and fish oil diet protected against increases in levels of TXB2 or PGF1 alpha during sepsis. Dietary restriction of linoleic acid or fish oil supplementation may play an important role in altering the inflammatory mediator response to sepsis.     

Effect of dietary fish oil supplementation on eicosanoid production by rat renal allografts

Acute renal allograft rejection is associated with significant alterations in renal arachidonic acid (AA) metabolism including increased production of the vasoconstrictor eicosanoid thromboxane (TX)A2. TX synthetase inhibition improves function of rejecting rat renal allografts but is difficult to accomplish pharmacologically. Therefore, we evaluated the potential use of dietary fish oil (FO) as a more practical method for reducing renal thromboxane production. We examined the effects of dietary FO supplementation on eicosanoid production and hemodynamic function of rat renal allografts. Donor and recipient rats were fed a fat-free diet supplemented with beef tallow (BT) or FO. After 6 weeks on the experimental diet, kidneys from ACI donors were transplanted into PVG recipients. Six days after transplant, renal function and eicosanoid production were measured. FO feeding resulted in significant alterations in eicosanoid production by renal allografts. There was a marked and generalized reduction in prostaglandin (PG) and TX production by allografts when both donor and recipient were fed a diet supplemented with fish oil. An intermediate reduction in production of PGE2 (and perhaps PGI2), but not TXB2, was observed when only the recipient was fed FO. Feeding FO to the donor alone had no effect on renal PG or TX production. These data suggest that both donor and recipient fatty acid pools contribute to AA metabolism during rejection. Unlike specific TX inhibition, the generalized inhibition of AA metabolism that occurred with FO feeding was not associated with improvement in function or morphology of allografts. However, potential benefit at earlier stages or in milder forms of rejection is possible and was not evaluated.     

Chronic effects of omega-3 fatty acids (fish oil) in a rat 5/6 renal ablation model

It has been proposed that fish oil dietary supplementation in the chronic rat 5/6 renal ablation model may be either protective or toxic. These conflicting hypotheses were tested in rats who underwent renal ablation or sham surgery. Twenty rats received sham surgery, and 40 received 5/6 renal ablation. All rats were fed a regular laboratory diet up to 1 week postsurgery. At that time, one half of the renal ablation group was provided with an isocaloric diet supplemented with 24% MaxEPA (fish oil), 1% safflower oil, and antioxidants. The renal ablation rats developed hypertension, albuminuria, gammaglobulinuria, and a decline in glomerular filtration rate, which was less in the fish oil group compared with that in the regular laboratory diet group at 10 and 20 wk postsurgery. The fish oil renal ablation rats had significantly less glomerulosclerosis than did the regular laboratory diet renal ablation animals, and no more glomerular fibrin deposition than did the sham controls. The renal ablation regular laboratory diet rats had a significant dyslipidemia at 20 wk which was prevented in the fish oil renal ablation cohort. The fish oil renal ablation rats also demonstrated a significant decline in renal tissue arachidonic acid incorporation and a concomitant increase in eicosapentaenoic acid and docosahexaenoic acid incorporation. The mortality of the renal ablation group was greater than that of the sham controls but not significantly different for the fish oil or the regular laboratory diet groups. These results support the hypothesis that the fish oil diet containing specific antioxidant, vitamin E, and essential fatty acid supplementation is protective in the rat remnant nephron model and prevents the evolution of glomerulosclerosis with associated renal functional impairment, while preserving glomerular filtration.     

Interactions of hypercholesterolemia and hypertension in initiation of glomerular injury.

In the Dahl S rat (DS), salt induces systemic and glomerular capillary hypertension associated with progressive glomerulosclerosis, while Dahl R rats (DR) remain normotensive, without glomerular abnormalities. Studies in experimental models have suggested that hypercholesterolemia may play a role in the development of glomerulosclerosis; however, it is unclear whether hypercholesterolemia alone, in the absence of hypertension, can initiate injury. To answer this question we induced hypercholesterolemia in salt-supplemented DS (DSC) and DR (DRC) by feeding a high cholesterol (4%) chow. Control rats (DS, DR) received high-salt, normal cholesterol chow. After eight weeks, DS and DSC developed equivalent hypertension (161 +/- 3 vs. 153 +/- 3 mm Hg, respectively, P = NS), while DR and DRC remained normotensive (138 +/- 5 vs. 131 +/- 5 mm Hg, P = NS; P less than 0.05 vs. DS and DSC). Cholesterol fed rats developed marked and equivalent hypercholesterolemia compared to controls (DS vs. DSC, 71 +/- 3 vs. 289 +/- 91 mg/dl, P less than 0.05; DR vs. DRC, 52 +/- 2 vs. 327 +/- 54 mg/dl, P less than 0.05). Hypertensive rats (DS, DSC) developed worse proteinuria and glomerular injury than normotensive rats (DR, DRC), but hypercholesterolemia exacerbated proteinuria and glomerulosclerosis only in DSC and not in DRC. Proteinuria significantly correlated with serum cholesterol in hypertensive rats (DS, DSC, P less than 0.05), but not normotensive rats (DR, DRC, P = NS). Furthermore, DSC had increased renal vascular resistance compared to DS, while no differences were found between DRC and DR. Thus, in the Dahl rat, hypercholesterolemia alone does not initiate glomerular injury. In this model, hypercholesterolemia is a pathogenetic factor in glomerular injury only when it coexists with systemic hypertension.     

Renoprotective effect of low iron diet and its consequence on glomerular hemodynamics

It has been reported that anemia limits renal injury in rats with reduced renal mass. We studied the effect of a low iron diet, given to reduce hematocrit, on urinary protein excretion and glomerular function in male MWF/Ztm rats, which spontaneously develop proteinuria and glomerular sclerosis. At 20 weeks of age, micropuncture and glomerular volume measurements were performed in untreated rats fed standard chow and in rats fed an isocaloric diet with low iron (5 mg/kg) content. Two additional groups of rats were used for total kidney function and glomerular volume evaluation at 35 weeks of age. At 20 weeks of age animals on low iron diet showed significantly (P less than 0.01) reduced hematocrit (46 +/- 5% vs. 54 +/- 2%) and proteinuria (60 +/- 15 vs. 225 +/- 34 mg/24 hr) than control animals, and no statistically significant differences were observed in single nephron hemodynamics. At 35 weeks of age rats on low iron diet had significantly lower proteinuria than age matched controls (222 +/- 68 vs. 411 +/- 71 mg/24 hr, P less than 0.01) and developed less glomerular sclerosis (mean percentage of sclerotic glomeruli was respectively 14 +/- 7% and 31 +/- 17%, P less than 0.05). Glomerular volume was comparable in animals on the low iron diet and in controls both at 20 and 35 weeks of age. These data indicate that low iron diet protected male MWF/Ztm rats against glomerular injury without significant effects on glomerular hemodynamics and on glomerular volume.     

Modification of experimental nephrotoxicity with fish oil as the vehicle for cyclosporine

Cyclosporine-associated renal dysfunction is well recognized. While renal vasoconstriction appears to be a major pathogenic factor, the precise mechanism responsible for the altered hemodynamics is unclear. To investigate whether alterations in renal eicosanoid metabolism could be involved, we substituted fish oil rich in eicosapentaenoic acid (EPA), an inhibitor of cyclooxygenase metabolites, for the conventional olive oil cyclosporine vehicle. Male rats were pretreated with 1.0 cc fish oil or olive oil by gavage. After 14 days, cyclosporine (12.5 mg/cc vehicle) was added to the oil and animals received cyclosporine 50 mg/kg for an additional 14 days. Pair-fed control animals received fish oil or olive oil alone. Glomerular filtration rate (GFR) was severely reduced in the cyclosporine-in-olive-oil (CSA + OO) group (0.28 +/- .05 ml/min/100 g) vs. olive oil (OO) controls (0.70 +/- .04) (P less than 0.001). While GFR was reduced in the cyclosporine-in-fish oil group (CSA + FO) vs. fish oil (FO) controls (0.47 +/- .07 vs. 0.74 +/- .04), it was significantly higher than in the CSA + OO group (P less than 0.05). Trough whole-blood cyclosporine levels were not significantly different in the two groups. While CSA + OO appeared to elevate renal cortical content of thromboxane B2 (65.7 +/- 7.3 pg/mg tissue vs. 46.9 +/- 5.3 for OO), both the CSA + FO and FO groups had reduced levels (31.1 +/- 2.7 and 29.5 +/- 2.3, respectively). In addition, there was a striking reduction in proximal tubular vacuolar changes in the CSA +/- FO vs. CSA + OO group. We conclude that the use of EPA-rich fish oil as the vehicle for cyclosporine results in improved renal function and morphology and is associated with depressed renal cortical levels of vasoconstrictor thromboxane B2.     

Comparative efficacy of dietary treatments on renal function in rats with sub-total nephrectomy: renal polyunsaturated fatty acid incorporation and prostaglandin excretion

The efficacy of dietary intervention with either 6% protein restriction, fish oil or safflower oil was assessed in the remnant nephron model. Female Munich Wistar rats were prefed for one week prior to 5/6 nephrectomy and followed for the ensuing 28 days. Fish oil, safflower oil and protein restriction prevented the gammaglobulinuria but only fish oil lessened the albuminuria in this model. The remnant nephrons of the fish oil treated rats contained less arachidonic acid and greater quantities of eicosapentaenoic and docosahexaenoic acid than the safflower oil or lab chow fed control rats. The fish oil, and to a lesser extent the safflower oil, treated animals had a higher ratio of 6 keto PGF1 alpha to TX B2 metabolites in their urine. We suggest these changes may be responsible for the lessening in urine protein excretion. Fish oil feeding was more effective than severe protein restriction or safflower oil dietary supplementation in lessening both the gammaglobulinuria and albuminuria of the remnant nephron model.     

The effects of ciclosporin in experimental glomerulosclerosis

The acute and chronic effects of daily, oral ciclosporin (CS) therapy (25 mg/kg) on proteinuria, blood pressure, renal function and histology were studied in rats subjected to unilateral nephrectomy and 3 weekly intraperitoneal injections of the aminonucleoside of puromycin (PAN). PAN therapy resulted in heavy proteinuria by week 4 which declined by weeks 8 and 16. When CS therapy was started weeks after the last dose of PAN, acute, transient reductions in proteinuria and reversible rises in blood urea nitrogen (BUN) were observed. When CS or oil therapy was started with PAN and continued for 8 or 16 weeks, there were no differences in proteinuria; however, after 16 weeks, CS treated rats had significantly higher BUN levels [65 +/- 11 (23.2 +/- 3.9) vs. 41 +/- 5 mg/dl (14.6 +/- 1.8 mmol/l); p = 0.001], a higher percentage of sclerotic glomeruli (47 +/- 7 vs. 28 +/- 10%; p less than 0.0001) and extensive interstitial fibrosis. There was a strong correlation between glomerulosclerosis and extent of interstitial fibrosis (r = 0.951; p less than 0.0001). These studies demonstrate that rats with experimental focal glomerulosclerosis treated with CS show an acute, transient reduction in proteinuria; however, chronic (for 16 weeks) CS therapy significantly increases azotemia and results in an increase in glomerulosclerosis and interstitial fibrosis.     

Renal injury of diet-induced hypercholesterolemia in rats

Abnormalities in lipid metabolism frequently accompany renal disease and may be important in the pathogenesis of progressive renal injury. In the present study, the effects of a high cholesterol diet on renal histology, cortical lipids, and glomerular hemodynamic function were examined in normal rats with and without reduced renal mass. Cholesterol feeding for 19 weeks increased serum cholesterol from 66 +/- 10 mg/dl to 256 +/- 93 mg/dl in two-kidney rats, and from 73 +/- 15 mg/dl to 407 +/- 274 mg/dl in nephrectomy rats (P less than 0.01). Both sham-operated and unilateral nephrectomy rats fed a high cholesterol diet had a greater amount of glomerulosclerosis and tubulointerstitial damage than rats fed standard chow. Cortical cholesteryl esters were increased by the cholesterol diet, and correlated with the amount of glomerulosclerosis (r = 0.90, P less than 0.01) and tubulointerstitial injury (r = 0.64, P less than 0.05). Cholesterol feeding and nephrectomy both caused alterations in tissue essential fatty acids, and a panel of specific monoclonal antibodies indicated that renal injury and cortical lipid alterations were associated with an increase in glomerular macrophages. Finally, micropuncture experiments carried out in a separate group of rats fed high cholesterol for 8 to 10 weeks demonstrated increases in glomerular capillary pressure. These results suggest that additional investigations may ultimately determine how cholesterol deposition, altered fatty acid metabolism, macrophages, and increased glomerular pressure might combine to cause chronic progressive renal injury.     

Dietary protein manipulation in experimental nephrotic syndrome

Evidence that glomerulosclerosis may be accelerated by high-protein diet and ameliorated by low-protein diet has led to debate concerning appropriate dietary recommendations in nephrotic syndrome. In this study, dietary protein was manipulated in a chronic, non-uraemic experimental model of nephrotic syndrome. Groups of 12 AS rats received 12, 24 or 48% protein diet after nephrotic syndrome was induced by adriamycin. Animals were sacrificed 8 weeks after change of diet when all were normotensive and none were uraemic. Animals on 24 and 48% maintained initial body weight and had persistent nephrosis. There was renal hypertrophy and histology showed tubular casts, focal tubulo-interstitial injury and glomerulosclerosis. Animals on 48% diet had more renal hypertrophy and worse histological damage but no differences in other parameters compared to 24% diet. On a 12% protein diet animals lost 15 +/- 3% of initial body weight (from 221 +/- 6 to 188 +/- 6 g; p less than 0.001). There was less proteinuria (p less than 0.0001), and lower serum cholesterol (p less than 0.0001) and triglyceride (p less than 0.01). Serum albumin was not different but total protein was lower than on 24 and 48% diet (p less than 0.01). Renal histological damage, although less severe than on 48% diet, did not differ from 24% diet. There was fatty infiltration of the liver. In view of the effects of low-protein diet in this model of nephrotic syndrome, dietary protein restriction should be applied with caution in human nephrotic syndrome.     

Effects of omega-3 fatty acid supplementation on tumor-bearing rats

BACKGROUND: Dietary fish oil (rich in omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid) suppresses synthesis and activity of proinflammatory cytokines that induce anorexia. We hypothesized that dietary fish oil reverses the feeding pattern of tumor anorexia, increasing food intake and retarding tumor growth. STUDY DESIGN: Thirty-two Fischer rats were placed in Automated Eater Meter cages and randomly divided into four groups: tumor bearing (TB) rats eating normal chow diet (TB-Chow); TB rats eating chow diet supplemented with omega-3 fatty acids (TB-omega-3FA); Controls, non-tumor bearing (NTB) rats eating normal chow (NTB-Chow); and NTB rats with omega-3 fatty acid supplementation (NTB-omega-3FA). Doses of 10(6) methylcholanthrene (MCA) sarcoma cells were subcutaneously injected in TB rats. Daily food intake, meal size (MZ), meal number (MN), body weight, and tumor volume were measured, and rats were euthanized at onset of anorexia. Data were statistically analyzed using analyses of variance (ANOVA) and t-tests. Data are reported as mean +/- SE. RESULTS: Tumor appeared significantly earlier in TB-Chow than in TB-omega-3FA rats (7.5 +/- 0.3 days versus 11.6 +/- 0.8 days, p < 0.05). Daily food intake declined significantly in TB-Chow versus TB-omega-3FA rats 18 days after tumor inoculation and, at onset of anorexia, was 9.41 +/- 1.77 g/day versus 13.32 +/- 0.81 g/day, p < 0.05. Food intake decreased initially by decrease in meal number (at day 15) followed by a decrease in meal size (at day 18). At onset of anorexia, meal size and meal number were significantly decreased in TB-Chow versus TB-omega-3FA rats (0.75 +/- 0.067 g/meal versus 1.05 +/- 0.08 g/meal, p < 0.05) and (9.5 +/- 1.32 versus 12.79 +/- 0.93 meals/day, p < 0.05), respectively. Tumor volume was significantly smaller in TB-omega-3FA versus TB-Chow rats (7.6 +/- 0.6 cm(3) versus 16.5 +/- 1.0 cm(3), p < 0.05), as was tumor weight (7.5 +/- 2.2 g versus 18.1 +/- 1.6 g, p < 0.05). CONCLUSIONS: In TB rats, omega-3FA improved food intake; restored normal eating pattern, delayed onset of anorexia, tumor appearance, and growth; and prevented body weight loss. Supplementation of omega-3 fatty acids has therapeutic potential in cancer anorexia.     

Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats

Hypertension frequently accompanies chronic glomerulonephritis. Mesangial injury and glomerulosclerosis are common in glomerulonephritis and are often harbingers of progressive glomerular destruction. Thus, in a model of mesangial immune injury we studied the relationship between hypertension, mesangial injury, and glomerulosclerosis. We induced mesangial ferritin-antiferritin immune complex disease (FIC) in Dahl salt-sensitive (S) and salt-resistant (R) rats. S and R rats with FIC were fed chow containing 0.3% NaCl until 14 weeks of age and then switched to 8.0% NaCl chow until 28 weeks of age. Groups of control S and R rats (no FIC) were either fed 0.3% NaCl for 28 weeks or switched to 8.0% NaCl chow at 14 weeks of age. Blood pressure, serum creatinine, urinary protein, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined at 14 and 28 weeks of age. R rats with or without FIC did not develop hypertension; mesangial injury was minimal. At 14 weeks of age, only S FIC rats developed hypertension, proteinuria, significant mesangial expansion and early glomerulosclerosis. At 28 weeks of age, proteinuria, mesangial expansion, and glomerulosclerosis were significantly more severe in hypertensive S rats with FIC than in those without FIC. These studies show that despite a normal salt intake, mesangial injury hastened the onset of hypertension, but only in rats genetically predisposed to hypertension (S FIC at 14 weeks). High dietary salt further aggravated hypertension, which, in turn, magnified both mesangial injury and glomerulosclerosis. Clinically, the different rates of progression of human glomerulonephritis associated with hypertension may be in part dependent on similar mechanisms.     

Captopril, but not diltiazem, favorably affects the course of early chronic renal disease in rats

The concepts that increased intracellular Ca2+ content and increased glomerular capillary pressure play an important role in the progression of chronic renal diseases has led to the suggestion that treatment with calcium-blocking agents (diltiazem; CBB) or converting enzyme inhibitors (captopril; CEI) may be indicated to prevent renal failure. We studied the effects of CCB and CEI on the early course of adriamycin (ADR) nephropathy, where glomerular pressure has been shown to be unchanged, blood pressure was only mildly elevated and renal failure incipient. Animals were studied 2, 7, 12, 16 and 20 weeks after the second injection of ADR, 2 mg/kg. In treated rats, blood pressure remained normal. At the end of the study, proteinuria and serum creatine were lower in ADR-CEI than in ADR rats (149 +/- 42 vs. 616 +/- 90 mg/day, p less than 0.01 and 0.36 +/- 0.04 vs. 0.58 +/- 0.02 mg%, p less than 0.01, respectively). ADR-CCB had values similar to those of untreated ADR rats. Mesangial expansion and focal glomerulosclerosis were present only in ADR and ADR-CCB rats, whereas in ADR-CEI rats the glomeruli were virtually normal. Glomerular 45Ca uptake was increased in ADR, decreased in ADR-CCB rats, and normal in ADR-CEI. Glomerular 6-keto PGF1 alpha and TxB2 were significantly increased in ADR rats, and both treatments decreased TxB2. The results suggest that endogenous angiotensin II is important for the early progression of glomerular injury toward renal insufficiency, while tissue Ca2+ accumulation may play an important role in more advanced phases.     

Exercise training ameliorates progressive renal disease in rats with subtotal nephrectomy

To determine the effect of chronic exercise training on renal function in animals with moderate renal insufficiency, rats with 75% renal ablation were either exercise trained by swimming for two months or remained sedentary. Glomerular filtration rate was significantly higher in trained (1.89 +/- 0.07 ml/min) than in sedentary rats (1.52 +/- 0.11 ml/min). No change was observed in renal blood flow or the degree of hypertension. Proteinuria was reduced in trained (13.6 +/- 4.9 mg/24 hr) compared to sedentary animals (33.5 +/- 9.2 mg/24 hr). The degree of glomerulosclerosis was much less prominent in trained animals. Plasma, low-density lipoprotein cholesterol-levels and total triglycerides were reduced in trained compared to sedentary rats. This study suggests that chronic exercise training ameliorates the progression of renal disease and improves plasma lipids in rats with moderate renal insufficiency. The mechanism for this improvement in renal function appears to be independent of the influence of systemic blood pressure.     

Pirfenidone prevents the progression of irreversible glomerular sclerotic lesions in rats

Summary: Pirfenidone (PFD) is a new drug which has been shown to prevent or even reverse the extracellular matrix accumulation in several organs. to examine the effect of PFD on the progressive glomerulosclerosis, we treated model rats with irreversible chronic renal disease per orally with 500 mg/kg bodyweight of PFD per day. the model rats were made by intravenous injection of anti-Thy-1 monoclonal antibody 1-22-3 at 1 h following unilateral nephrectomy, which results in chronic progressive glomerulosclerosis. Twenty-four hours later, 32 female Wistar rats were divided into two groups and were fed standard chow with (PFD group: P) or without PFD (control group: C). All rats were sacrificed on day 42. No significant difference in the bodyweight or the amount of chow intake was observed between the two groups. the remnant kidney was significantly ( P <0.05) heavier in C (2.11 ± 0.15 g) than in P (1.70 ± 0.13 g). This finding, together with light microscopic findings, showed that PFD administration resulted in the prevention of renal hypertrophy. On day 42, proteinuria in P (124.3 ± 31.9 mg/day) was significantly lower than in C (214.6 ± 8.1 mg/day), and P maintained significantly better renal function than C as judged by serum urea nitrogen and creatinine levels. Mean matrix score was less in P (178 ± 17) than in C (225 ± 22). Crescent formation was observed in 17% of glomeruli in P and in 35% in C. Tubulointerstitial lesions were also less severe in P. Furthermore, inflammation and sclerosis indices detected by immunohistochemistry (e.g. ED-1, OX8, TGF-beta α-smooth muscle actin, collagen type I, were less in P). These data suggest that PFD may be a promising agent for the prevention of progressive and irreversible glomerulosclerosis.     

Down-regulation of lipoprotein lipase and VLDL receptor in rats with focal glomerulosclerosis.

BACKGROUND: Patients and animals with nephrotic syndrome and those with chronic renal failure (CRF) often exhibit hypertriglyceridemia and impaired very low-density lipoprotein (VLDL) clearance. Imai rats that were originally derived from Sprague-Dawley rats develop spontaneous proteinuria, hyperlipidemia, progressive renal insufficiency and histologic changes of focal glomerulosclerosis (FGS), closely resembling human FGS. This study was undertaken to test the hypothesis that elevation of plasma triglyceride and VLDL concentrations in the Imai rats is associated with deficiency of lipoprotein lipase (LPL) and VLDL receptor which are the main pathways of triglyceride-rich lipoprotein clearance. METHODS: Male Imai and Sprague-Dawley control rats were fed regular rat chow and studied at 10 and 34 weeks of age. Tissue LPL and VLDL-r protein abundance (Western analysis) and post-heparin lipolytic activity were determined. RESULTS: At 10 weeks of age, Imai rats showed mild proteinuria, moderate hyperlipidemia, normal creatinine clearance and blood pressure. By 34 weeks of age, the study animal exhibited severe proteinuria, marked hyperlipidemia, significant renal insufficiency and hypertension. This was associated with a severe progressive reduction in skeletal muscle and adipose tissue LPL and VLDL-r protein abundance and depressed plasma post heparin, lipolytic activity. CONCLUSION: Progressive hyperlipidemia in the Imai rats with spontaneous FGS is accompanied by severe combined LPL and VLDL-r deficiencies that can, in part, account for the associated hypertriglyceridemia and elevated plasma VLDL concentrations.