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.     

Effects of dietary protein on the progression of renal failure in the Fawn-Hooded rat

Fawn-Hooded (FH) rats on a normal protein intake develop focal glomerulosclerosis, proteinuria and hypertension and die prematurely because of renal failure. In the present study we examined the effect of a life long feeding of a low (12%)-protein (LP) diet and a high (36%)-protein (HP) diet on renal function, urinary protein excretion (UprotV), systolic blood pressure (SBP) and survival time. Compared to the LP diet, the HP diet initially raised the glomerular filtration rate (GFR) and the UprotV, while the SBP was about the same. The UprotV of rats on the HP diet increased steadily and the GFR started to decline after 40 weeks. The LP diet resulted in a prolonged period of stable renal function, limited proteinuria and an increased life span. In the 2nd year of life, the level of hypertension was less in FH rats on the HP diet. Throughout the study there was no relationship between the SBP and the UprotV. The low UprotV in FH rats on the LP diet points to a lower level of glomerular capillary pressure. The attenuated development of glomerular hypertension on the LP diet slows down the subsequent renal damage in FH rats. This is in agreement with the view that glomerular hypertension is an essential hemodynamic derangement responsible for progressive deterioration of glomerular function. As in other rat models, i.e. renal ablation or unilateral nephrectomy, the LP diet slowed down the development of renal failure but did not prevent it.     

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.     

Atorvastatin preserves renal function in chronic complete unilateral ureteral obstruction

PURPOSE: The pleiotropic effects of hMG-CoA (3-hydroxy-3-metylglutaryl coenzyme A) reductase inhibitors may provide renal protection in chronic kidney disease. We examined whether atorvastatin administration preserved renal function in rats with chronic unilateral ureteral obstruction. MATERIALS AND METHODS: Renal clearance experiments were performed in sham operated rats and rats subjected to 3 or 12-day unilateral ureteral obstruction. Hemodynamics parameters and urinary microalbumin levels from the obstructed kidney were also measured. The rats were maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg daily). RESULTS: Atorvastatin administration did not alter plasma total cholesterol but it significantly decreased triglyceride levels. In sham operated and 3-day unilateral ureteral obstruction rats atorvastatin treatment did not have effects on the glomerular filtration rate or effective renal plasma flow and it also did not affect urinary microalbumin levels. In rats with 12-day unilateral ureteral obstruction the glomerular filtration rate but not effective renal plasma flow was significantly higher and urinary microalbumin was significantly lower in atorvastatin treated rats than in those without atorvastatin treatment. CONCLUSIONS: Atorvastatin treatment decreased microalbuminuria and helped preserve filtration function in chronic unilateral ureteral obstruction without altering plasma cholesterol levels, suggesting that pleiotropic renal protection is offered by this statin.     

Effect of eicosapentaenoic acid on the progression of chronic renal failure in rats.

Eicosapentaenoic acid (EPA) can induce a shift in prostaglandin and leukotriene synthesis. The effects of EPA supplementation of the diet on the progression of chronic renal failure (CRF) were evaluated in a model of 5/6 renal mass ablation in rats. After 30 or 60 days of CRF, elevation in single-nephron glomerular filtration rate due to an increase in glomerular plasma flow and hydraulic pressure was observed. These hemodynamic alterations were followed by a rise in proteinuria and glomerular sclerosis. EPA treatment for 30 or 60 days did not substantially modify the hemodynamic or morphological profiles induced by renal mass ablation. In the present non-immune model of CRF, preglomerular vasodilation with glomerular hyperperfusion and hypertension were responsible, at least in part, for the presence of proteinuria and glomerular sclerosis. No additional vasodilation was observed in the present model of CRF, and, thus, hemodynamic effects induced by EPA did not modify renal damage, in contrast to the EPA effects observed in immune-mediated models of CRF.     

Effects of dietary fatty acids in an animal model of focal glomerulosclerosis

The obese Zucker rat develops hyperlipidemia, proteinuria and focal glomerulosclerosis without prior changes in renal hemodynamics. To study the effects of oral fatty acid intake on the development of renal injury in this model, rats were fed standard chow or chow supplemented with either 14% fish oil or 14% beef tallow after unilateral nephrectomy at the age of 10 weeks. At 32 weeks post-nephrectomy animals were sacrificed and renal tissue saved to assess histology and glomerular eicosanoid production. Fish-oil treated rats had lower mean plasma cholesterol levels and developed less proteinuria than control or tallow-fed animals although there was no difference in plasma creatinine or blood pressure. Histological analysis showed significantly fewer sclerosed glomeruli in the fish oil group (4.0 +/- 0.8% vs. control 19.4 +/- 4.1%, P less than 0.0005 and vs. beef tallow 10.8 +/- 1.9%, P less than 0.005). Glomeruli derived from rats on fish oil supplements produced smaller amounts of prostaglandin (PG)E2 and of the stable metabolites of PGI2 (6-oxo-PGF1 alpha), PGF2 (PGF2 alpha) and thromboxane (TX)A2 (TXB2) than those from tallow-fed animals. This study demonstrates that oral fatty acid intake may influence the development of glomerulosclerosis. The apparent beneficial effects of fish oil have not been fully defined, but may relate to favorable changes in plasma lipid concentration and renal eicosanoid production.     

Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats

BACKGROUND: Hyperuricemia has been associated with renal disease. Because glomerular hemodynamic alterations critically contribute to initiation and progression of renal disease, we evaluated the effect of mild hyperuricemia in glomerular microcirculatory changes in rats under normal conditions and with renal injury induced by subtotal renal ablation (RK). METHODS: Hyperuricemia was induced in normal and remnant kidney (RK) rats on a normal sodium diet by administration of oxonic acid (OA). To prevent hyperuricemia, allopurinol (AP) was administered concomitantly. Glomerular hemodynamics were evaluated by micropuncture techniques. Systolic blood pressure (SBP), proteinuria, arterial morphology, and serum uric acid were measured. In RK rats, glomerulosclerosis, fibrosis, and inflammatory cell infiltration (CD5+) were also assessed. RESULTS: In normal rats, hyperuricemia resulted in afferent arteriole thickening associated with renal cortical vasoconstriction [single nephron glomerular filtration rate (SNGFR) -35%, P < 0.05) and glomerular hypertension (P < 0.05). Allopurinol treatment prevented structural and functional alterations. In RK rats, hyperuricemia produced more renal vascular damage than control animals coupled with severe cortical vasoconstriction (SNGFR -40%, P < 0.05) and persistent glomerular hypertension. Allopurinol partially prevented cortical vasoconstriction, and fully prevented arteriolopathy and glomerular hypertension associated with significantly less infiltration of CD5+ cells. CONCLUSION: Hyperuricemia induces arteriolopathy of preglomerular vessels, which impairs the autoregulatory response of afferent arterioles, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening produces severe renal hypoperfusion. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis, as well as arterial hypertension. These studies provide a potential mechanism by which hyperuricemia can mediate hypertension and renal disease.     

Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats

Interventions to block the renin-angiotensin system (RAS) halt the progression of renal lesions in renal damage models. It has recently also been reported that established glomerulosclerosis can be reversed by pharmacologic blockade of the RAS. It was the aim of this study to confirm that high doses of angiotensin-converting enzyme (ACE) inhibitors reverse established glomerulosclerosis and to extend the findings by providing quantitative information on glomerular geometry, podocytes and other glomerular cells, renal vessels and tubulointerstitial tissue. Male Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) (n = 27) or sham operation (n = 31) and fed using a pair-feeding protocol. Eight weeks after surgery, rats were either sacrificed or allocated to two arms: enalapril treatment (48 mg/kg body wt per day administered in the drinking fluid for 4 wk) or no treatment. Renal morphology was evaluated after 8 or 12 wk, respectively, by stereology in tissue fixed by pressure-controlled perfusion. Both systolic BP and albumin excretion rate were significantly higher in SNX compared with sham-operated controls. They were significantly reduced in SNX after delayed enalapril treatment. The glomerulosclerosis (GSI), tubulointerstitial (TII), and vascular (VI) damage indices were significantly higher in all SNX groups than in sham-operated controls. At the end of the experiment (12 wk after SNX) GSI, TII, and VI were significantly lower in SNX with delayed enalapril treatment (0.77 +/- 0.18, 0.63 +/- 0.19 and 0.43 +/- 0.16, respectively) compared with untreated SNX (1.64 +/- 0.14, 1.16 +/- 0.34 and 0.67 +/- 0.29, respectively). GSI, TII, and VI were also significantly lower in SNX with delayed enalapril treatment compared with SNX sacrificed without treatment 8 wk after SNX. The same was true for glomerular volume. The number of podocytes was not affected by SNX, but podocyte volume was increased. Both indices remained unaffected by treatment. The numbers of cells within the mesangium and endothelial cells per glomerulus were significantly lower in SNX after delayed enalapril treatment compared with untreated SNX. These results strongly suggest regression of preexisting lesions, i.e., glomerular, tubular, and vascular remodeling as well as reversal of glomerular hypertrophy by ACE inhibitor treatment. The study confirms that high-dose ACE inhibitor treatment causes partial reversal of glomerular as well as interstitial lesions in subtotally nephrectomized rats.     

Hypothyroidism retards progressive glomerulosclerosis in the rat by a reduction in food intake

Hypothyroidism diminishes proteinuria and prolongs survivalin several immune models of progressive renal failure. In thewell-characterized non-immune model of 5/6 nephrectomy we studiedthe effects of thyroidectomy (Tx) on the development of proteinuriaand glomerulosclerosis (GS). Hypothyroidism was confirmed bylower values of thyroxine in Tx rats compared to sham Tx ratsat 9 weeks (12.6±6.7 nmol/l Tx versus 37.7±10.8nmol/l sham Tx) and 12 weeks after operation (7.2±4.9nmol/1 Tx versus 14.4±4.1 nmol/l sham Tx). Tx resultedin a reduction in mean arterial blood pressure and proteinuriaand a lower incidence of GS (4.2±3.1% Tx versus 17.1±10.0%sham Tx) 12 weeks after nephrectomy, along with a decrease infood intake (104±13 g/week Tx versus 138±10 g/weeksham Tx). In the same experiment a third group of sham Tx ratswas pair fed to the Tx rats, resulting in values similar tothose of Tx rats for proteinuria and the incidence of GS (6.0±4.9%pair fed sham Tx). Thyroxine levels at 9 and 12 weeks were comparableto those in sham Tx rats fed ad libitum. No association wasfound between the incidence of GS and glomerular volume. Studiesof the inulin clearance in a second set of experiments showedthat glomerular filtration rate and renal plasma flow are lowerin hypothyroid rats compared to sham Tx rats. We conclude that hypothyroidism has a renal protective effectdue to a decrease in food intake resulting in alterations inrenal haemodynamics.     

Acute renal vascular response to ACE inhibition in two rat strains with different susceptibility to the development of glomerulosclerosis.

Normotensive male Wistar rats are susceptible to the development of glomerulosclerosis, a process which can be accelerated by partial renal ablation, while normotensive male Wistar Kyoto (WKy) rats are resistant to glomerulosclerosis. Long-term treatment with angiotensin-I-converting enzyme inhibitors prevents the development of glomerulosclerosis. We studied the acute renal vascular response to bolus injections of captopril (1, 3, and 10 mg/kg). Mean arterial blood pressure (MAP) was significantly less in Wistar rats compared to WKy and not influenced by unilateral nephrectomy. Renal vascular resistance (RVR) and the filtration fraction (FF) were significantly greater in sham and unilateral nephrectomy Wistar rats as compared to WKy. Captopril significantly reduced the RVR in all four groups, but at comparable doses, RVR remained greater in the Wistar sham and Wistar rats following unilateral nephrectomy compared to sham and uninephrectomized WKy respectively. Captopril reduced FF in Wistar rats only. These data indicate an enhanced level of activity of the renal renin-angiotensin system in glomerulosclerosis-susceptible Wistar rats compared to glomerulosclerosis-resistant WKy rats, suggesting that vascular reactivity involving the renin-angiotensin system is an important determinant of the genetically determined differences in susceptibility to glomerulosclerosis in these two rats strains. The strain-dependent difference in RVR at the highest dose of captopril indicates that additional, possibly structural features may play a role in the difference in susceptibility to glomerulosclerosis.     

Differential effects of calorie restriction on glomeruli and tubules of the remnant kidney.

We have previously shown that 40% calorie restriction (CR) prevents renal injury 21 weeks after 5/6 nephrectomy (Nx) in rats, regardless of whether protein intake was concurrently restricted or not. Growth retardation appeared to be a necessary prerequisite for the protective effects of CR. To further study these mechanisms, we performed 5/6 Nx in male F344 rats and pair-fed them with a control diet (ad lib group) or a high protein diet restricted by 40% so that protein intake was similar, but calorie consumption was reduced (CR group). Four weeks after 5/6 Nx, when glomerulosclerosis had not yet developed, we compared various parameters as follows in both dietary groups and sham operated rats: urinary protein excretion (uPr), GFR (14C inulin clearance), mean nephron GFR (MNGFR; GFR divided by total number of glomeruli), glomerular volume (VG), tubulointerstitial index (TII), a measure of tubular damage kidney weight (kidney wt), kidney IGF-I content by RIA, and IGF-I immunohistochemistry. CR ameliorated the increase of MNGFR, but not glomerular hypertrophy. TII, kidney wt and kidney IGF-I content were increased in the ad lib Nx group; these changes were alleviated by CR. Two weeks after 5/6 Nx, immunohistochemistry for IGF-I showed increased staining in superficial distal nephrons in the ad lib group, and this was also suppressed by CR. The occurrence of tubulointerstitial pathology prior to glomerulosclerosis, and the beneficial effects of CR on all parameters except Vg indicate a dissociation of mechanisms which result in tubular versus glomerular hypertrophy and damage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dietary lipids on renal function in rats with subtotal nephrectomy

Female rats with 1-3/4 nephrectomy were divided in two groups and pair fed for five weeks diets differing in their linoleic acid content. Five weeks after subtotal nephrectomy, values for glomerular filtration rate and renal plasma flow were significantly higher and the values of blood pressure significantly lower in rats fed a diet rich in linoleic acid. Systolic blood pressure averaged 156 +/- 5.6 mm Hg in high and 215 +/- 8.1 mm Hg in low linoleic acid-fed rats. Differences in the values of blood pressure between the two groups were observed three weeks after subtotal renal ablation and persisted throughout the period of observation. Inulin clearance averaged 0.89 +/- 0.07 ml/min in the high and 0.44 +/- 0.05 ml/min in the low linoleic acid group. Protein excretion in the urine was significantly less in rats fed the high linoleic acid diet (36.9 +/- 4.4 mg/24 hr) than in those fed the low linoleic acid diet (90.1 +/- 12.5 mg/24 hr). The weight of the remnant kidney five weeks after subtotal renal ablation was greater in rats fed a low linoleic acid diet as compared to those fed a high linoleic acid diet (P less than 0.05). Glomerular lesions were more severe in rats fed a low linoleic acid diet than in those fed a high linoleic acid diet. Feeding high linoleic acid diets to normal and subtotally nephrectomized rats increased the content of linoleic and arachidonic acid in renal cortex and medulla.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of the supplementation of kidney mass on blood pressure and progression of kidney disease.

BACKGROUND: To test the hypothesis that nephron mass is an independent determinant of arterial pressure, the effects of augmenting renal mass by isograft transplantation were studied in the model of secondary hypertension. METHODS: The effects of isograft transplantation or sham operation on blood pressure, proteinuria, remnant kidney mass, glomerular filtration rate and glomerulosclerosis were assessed in 5/6 nephrectomized (5/6 NPX) rats. RESULTS: Systolic blood pressure was lowered on average by approximately 35 mmHg and glomerular hyperfiltration was attenuated in the remnant kidneys of transplant recipients. Markedly lower urinary protein excretion rates and glomerulosclerosis scores in the remnant kidney accompanied these supplemental transplants to values roughly one-third of those from sham-operated rats. CONCLUSIONS: The data show that reduced renal mass per se is the major factor in the development and maintenance of arterial hypertension and glomerular injury in 5/6 NPX rats and these changes can be reversed by supplementing renal mass. The data provide strong support for the notion that renal mass is a significant, independent determinant of arterial pressure.     

Hemodynamics of hyperuricemia

Prolonged hyperuricemia is associated with the development of hypertension, renal arteriolosclerosis, glomerulosclerosis, and tubulointerstitial injury. It confers a greater risk than proteinuria for developing chronic renal disease and is associated with the development of hypertension. Mild chronic hyperuricemia without intrarenal crystal deposition was induced in rats by inhibiting uricase with oxonic acid. Hyperuricemic rats developed hypertension, afferent arteriolar thickening, and mild renal interstitial fibrosis. Additionally, hyperuricemia accelerated renal damage and vascular disease in rats undergoing renal ablation. To better understand the role of hyperuricemia in the kidney, micropuncture studies were performed. Hyperuricemia resulted in renal cortical vasoconstriction (single nephron glomerular filtration rate (SNGFR) 35%, P < .05) and glomerular hypertension (P < .05). The possibility that hyperuricemia could modify renal hemodynamic disturbances during progression of renal disease was tested in rats with 5/6 nephrectomy. Hyperuricemia accentuated the renal vascular damage and caused cortical vasoconstriction (SNGFR 40%, P < .05) and persistent glomerular hypertension. In conclusion, hyperuricemia impairs the autoregulatory response of preglomerular vessels, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening results in severe vasoconstriction. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis as well as arterial hypertension.     

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.     

Effects of salt restriction on renal growth and glomerular injury in rats with remnant kidneys.

Male Munich-Wistar rats underwent right nephrectomy and infarction of two thirds of the left kidney. Rats were randomly assigned to ingest standard chow (REM) or a moderately salt restricted chow (LS). A third group of rats were fed the low salt diet and were injected with an androgen (LSA). Eight weeks after ablation, glomerular volume and glomerular capillary radius were markedly increased in REM. This increase was prevented by the low salt diet, however, the antihypertrophic effect of the diet was overcome by androgen. Values for glomerular volume and capillary radius were similar in LSA and REM. Morphologic studies revealed that approximately 25% of glomeruli were abnormal in REM. Much less injury was observed in salt restricted rats, however, the protective effect of the low salt diet was significantly abrogated when renal growth was stimulated in salt restricted rats by androgen. Micropuncture studies revealed that glomerular pressure was elevated in all three groups and not affected by diet or androgen. Serum cholesterol was also similar in the three groups. These findings indicate that renal and glomerular hypertrophy are correlated with the development of glomerular injury after reduction in renal mass and suggest that dietary salt restriction lessens renal damage, at least in part, by inhibiting compensatory renal growth.     

Effects of keto acid supplements on renal function and histology in azotemic rats fed high-protein diets

The mechanism by which keto-acid-supplemented diets may retard the progression of renal failure is not known. We examined whether the protective effect of keto acids may be independent of a low nitrogen intake. Azotemic subtotally nephrectomized Sprague-Dawley rats were pair-fed a 30% casein diet supplemented with a 10% keto acid mixture (n = 10) or 10% cornstarch (n = 10) for 18 weeks. No differences were observed between the two groups of rats with regard to survival, weight gain, plasma urea, blood pressure, albuminuria, or, at the termination of the study, PAH and inulin clearances. Creatinine clearances, measured weekly during the study, were transiently higher in the keto acid group. There was no difference in the incidence or severity of segmental glomerulosclerosis or tubular atrophy in the two groups. These results indicate that the keto acid mixture used did not exert a protective effect against glomerular sclerosis and progressive albuminuria in azotemic rats fed high-protein diets.     

Progressive glomerular sclerosis in experimental antiglomerular basement membrane glomerulonephritis

A model of chronic progressive glomerular sclerosis in experimental antiglomerular basement membrane (anti-GBM) glomerulonephritis was developed in Wistar rats. Wistar rats given the accelerated form of anti-GBM anti-body glomerulonephritis initially developed significant proteinuria and renal insufficiency associated primarily with a decrease in glomerular filtration rate (GFR) with normal renal clearance of para-aminohippuric acid and with markedly reduced filtration fraction. The glomerular functional abnormalities were associated with marked glomerular hypercellularity due to leukocytic infiltration as well as proliferation of intrinsic glomerular cells with crescent formation. Late in the course of the disease, by day 21, GFR had fallen further, associated with a parallel decrease in the clearance of para-aminohippuric acid and a normal filtration fraction. At this stage, glomerular hypercellularity had diminished and was replaced by glomerular sclerosis. The model appears to be a reproducible form of chronic glomerulosclerosis and demonstrates that the chronic phase of glomerular basement membrane (GBM) glomerulonephritis is distinctly different from that of the acute phase. It provides a controllable setting to study the glomerular sclerotic process independent of the initial inflammatory changes.     

Low protein diet mediated renoprotection in remnant kidneys: Renal autoregulatory versus hypertrophic mechanisms

BACKGROUND: The mechanism of low protein diet conferred renoprotection in the ablation model remains controversial. Blockade of glomerular hypertrophy, reduced preglomerular vasodilation, and preserved autoregulation have all been postulated. The potential differential impact of calcium channel blockers on these mechanisms and glomerulosclerosis was examined. METHODS: Rats with 5/6 renal ablation received either a 25% standard protein diet, an 8% low protein diet and a low protein diet with either verapamil or amlodipine. Renal autoregulatory and morphometric studies were performed at 3 weeks before the development of significant injury, and the assessment of glomerulosclerosis after 7 weeks of continuous blood pressure radiotelemetry in additional rats. RESULTS: The preserved renal autoregulation in low protein rats was abolished by both calcium channel blockers, with the impairment being either comparable to (low protein + verapamil) or greater than the standard protein rats (low protein + amlodipine). Neither calcium channel blocker blocked the inhibitory effects of low protein diet on renal blood flow, kidney weight, and glomerular volume. Results (mean +/- SE) for glomerular volume (microm-3x 10(-6)): low protein (N = 11), 1.6 +/- 0.1; low protein + verapamil (N = 10), 1.7 +/- 0.1; low protein + amlodipine (N = 12), 1.7 +/- 0.2; versus standard protein (N = 10), 2.2 +/- 0.1; P < 0.05. Only amlodipine, but not verapamil, reduced average systolic blood pressure (143 +/- 2 mm Hg versus low protein rats, 168 +/- 5 mm Hg, and standard rats, 170 +/- 6 mm Hg; P < 0.01). Nevertheless, the glomeruloprotection seen in low protein (N = 15) as compared to standard protein (N = 14) rats (9%+/- 3% versus 28%+/- 6% glomerulosclerosis; P < 0.01) was abolished in both low protein + verapamil (N = 14, 32%+/- 7%) and low protein + amlodipine rats (N = 16, 27%+/- 7%). CONCLUSIONS: Preservation of renal autoregulation and not inhibition of hypertrophy is the critical component in low protein diet-conferred glomeruloprotection.     

Hyperuricemia causes glomerular hypertrophy in the rat

BACKGROUND/AIMS: Rats with mild hyperuricemia develop systemic hypertension, interstitial renal disease, afferent arteriolopathy, and increased renin expression [Mazzali et al.: Am J Physiol 2002;6:F991-F997]. We hypothesized that hyperuricemia might also induce glomerular changes. METHODS: We reviewed renal biopsies of rats previously made hyperuricemic for 7 weeks with the uricase inhibitor, oxonic acid. Controls included normal rats and oxonic acid-treated rats administered allopurinol, benziodarone, hydrochlorothiazide, or enalapril. Glomeruli were examined for size (computer image analysis) and structure (histology). An additional group of rats were administered oxonic acid or control diet for 6 months. RESULTS: Renal biopsies showed that hyperuricemic rats had a 30% increase in glomerular tuft area (p < 0.01); these changes were prevented by allopurinol and benziodarone. Control of blood pressure with hydrochlorothiazide did not prevent the development of glomerular hypertrophy, whereas enalapril partially reduced the glomerular hypertrophy. Prolonged hyperuricemia was associated with the development of microalbuminuria (p < 0.05) and glomerulosclerosis (22 vs. 10%, p < 0.05) compared to control rats. CONCLUSIONS: Hyperuricemic rats develop glomerular hypertrophy that can be prevented in part by ACE inhibitor therapy. Prolonged hyperuricemia is associated with the development of glomerulosclerosis in the rat.