Nephrotic Rats Research Articles

Elevation of urinary IL-1β levels during transplant associated nephropathy in rat model of the nephrotic syndrome

A recurrence of nephrotic syndrome is a well-known phenomenon in patients who receive kidney transplantation. In this study, we attempt to establish a rat model of recurrent nephrotic change after renal transplantation using puromycin aminonucleoside (PA) induced nephrotic rats. We then examine the mechanism leading to recurrence. Female Sprague-Dawley rats (8 weeks) were divided into four groups: group A, allogenic renal transplantation of a normal kidney to PA-induced nephrotic rats; group B, PA injection only as a nephrotic control; group C, allogenic transplantation of a normal kidney to rats receiving a saline injection; group D, rats receiving only a saline injection. The serum and urinary levels of protein, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2 and interferon (IFN)-gamma were measured. The cytokine levels were assessed by performing enzyme-linked immunosorbent assays. Six days after renal transplantation, the kidneys were excised, tissue sections were stained with hematoxylin-eosin and the specimens were studied for pathological alterations. The urinary protein levels and the histological results of protein casts in renal tubules of the autologous kidneys of the nephrotic rats and the transplanted kidneys confirmed the recurrence of nephrotic syndrome in the transplanted kidney. After renal transplantation, urinary protein and IL-1beta levels were significantly elevated in recurrent transplanted kidney groups compared with those in the control groups, while the TNF-alpha, IL-2, and IFN-gamma levels were not elevated. In addition, serum levels of TNFalpha and IL-1beta were not elevated. These results suggested that IL-1beta may relate to the recurrent nephropathy in the transplanted kidney in the nephrotic rat.

Do severe systemic sequelae of proteinuria modulate the antiproteinuric response to chronic ACE inhibition?

ACE inhibition exerts an antiproteinuric and renoprotective effect. However, residual proteinuria is often present. As residual proteinuria is associated with a poor renal outcome, identification of its determinants is important. We found previously that the systemic sequelae of proteinuria enhance renal damage in untreated nephrotic rats. The impact of systemic nephrosis on renal therapy response, however, is unclear. In the present study we therefore investigated whether the severity of systemic nephrosis, estimated from plasma cholesterol, predicts residual proteinuria during ACE inhibition. Sixty male Wistar rats with established adriamycin nephrosis were studied. Six weeks after the induction of nephrosis, rats were stratified for proteinuria and treated for 2 weeks with lisinopril (75 mg/l) or vehicle. At the start of treatment, median proteinuria was 744 mg/day (95% confidence interval (CI) 609-860) and plasma cholesterol was 10.4 mmol/l (95% CI 8.0-12.6), reflecting the state of systemic nephrosis. Lisinopril, but not vehicle, reduced blood pressure and proteinuria (-62%; range -70 to -48; P<0.001). Residual proteinuria was 275 mg/day, with a wide range (47-1119 mg/day). Pre-treatment proteinuria and pre-treatment cholesterol correlated positively with residual proteinuria. By multivariate analysis (r(2) of model =0.92), both pre-treatment cholesterol and pre-treatment proteinuria were independent predictors of residual proteinuria. The quantitative impact of this multivariate analysis is illustrated by the difference in residual proteinuria between rats with a cholesterol:proteinuria ratio less than, compared with greater than, the median (residual proteinuria 298 mg/day (CI 129-496) vs 439 mg/day (CI 158-670), respectively). Blood pressure response was not predicted by the tested predictor variables. In this model of proteinuria-induced renal damage, not only proteinuria as such, but also the concomitant nephrotic alterations predict residual proteinuria. Further studies, applying specific interventions, are needed to determine which components of the systemic derangements could play a causal role in the modulation of therapy response.

Evaluation of the pituitary-testicular function during experimental nephrosis

To investigate the pituitary-testicular function in nephrotic rats, a sequence of experiments was undertaken in adult male rats after a single dose of puromycin aminonucleoside (PAN). Endocrine modifications were evaluated chronologically throughout the experimental disease in order to determine the appearance of hormone alterations which lead to the axis dysfunction. Serum concentration of LH, FSH, androstenedione, total and free testosterone, estradiol as well as urine testosterone were measured by specific RIAs on days 3, 7 and 10 after treatment on nephrotic and control groups. Prolactin was also evaluated on day 10. Likewise, total weight of various androgen responsive tissues from both groups was recorded, and the number of androgen receptor (AR) binding sites were determined. To know the functional status of the hipophyseal-testicular unit, groups of nephrotic and control rats were stimulated with LHRH (300 ng/100 g b.w.) or with one or four doses of hCG (8 UI), respectively. Additionally, the relative in vitro biological activity of FSH from nephrotic and control rats before and after LHRH stimulus was determined. The results from the hormonal profile revealed clear endocrine disorders characterized by a progressive diminution of all serum hormones except prolactin and urine testosterone, which remained unmodified. The weight of the main androgen responsive tissues, the ventral prostate and the seminal vesicle, decreased parallelly to androgen diminution. The binding analysis of AR shows a significant elevation of the available androgen sites in all analyzed tissues except kidney and hypothalamus. The secretion of LH and FSH from nephrotic animals after LHRH administration was lower than that from intact animals at the registered times. Interestingly, the biological activity of FSH from nephrotic rats was not detectable at both, before and after LHRH administration. Testicular response to hCG stimuli, in terms of testosterone synthesis was not significantly different in the two groups analyzed with respect to the intact animals. By contrast, no response was observed in terms of estradiol production at either one or four doses of hCG. On the whole, the results presented herein allow us to conclude that experimental nephrosis has a harmful effect on the pituitary-testicular axis, and strongly suggests that the endocrine dysfunction is initiated at the hypophyseal level; even though a specific testicular damage is also present.

Dietary Quercetin Augments Activator Protein-1 and Does Not Reduce Nuclear Factor-κB in the Renal Cortex of Rats with Established Chronic Glomerular Disease

Background/Aims: Quercetin, a naturally occurring dietary flavonoid, is a potent in vitro inhibitor of the transcription factors, nuclear factor (NF)-ĸB and activator protein (AP)-1. Here we investigated the efficacy of quercetin to suppress renal cortical NF-ĸB/AP-1 activation and tubulointerstitial injury, in vivo, in a nephrotic rat model of chronic glomerular disease. Methods: Adult male Wistar rats with (n = 27) or without (n = 15) Adriamycin nephropathy (AN) were stratified into six groups (according to proteinuria and endogenous creatinine clearance, measured on day 10) and pair-fed a semipurified diet supplemented with or without quercetin (0.5, 2%) from day 14 to 36. Results: Quercetin-fed rats had minimal weight gain during the study (p < 0.05). In AN, proteinuria, the decline in endogenous creatinine clearance, hypercholesterolaemia and cortical tubulointerstitial injury were not reduced by quercetin. Quercetin had no effect on renal cortical NF-ĸB activation, but unexpectedly exacerbated the induction of AP-1 in AN (by 67%, p < 0.05). In normal rats, quercetin increased proteinuria (by 75%, p < 0.05), renal cortical AP-1 activation (by 198%, p = 0.06), and malondialdehyde production (by 110%, p < 0.05). Conclusion: These data suggest that supplementation of the diet with quercetin is not an effective therapeutic strategy alone to reduce NF-ĸB/ AP-1 activation in chronic glomerular diseases, and paradoxically could be associated with adverse renal effects.

Catabolism of brain natriuretic peptide (BNP) in normal and nephrotic rat kidney

The major metabolic change that characterizes nephrotic syndrome (NS) is hypoalbuminemia. Edema, which is a well-recognized clinical feature, often results in disorder of peripheral circulation and congestive heart failure. We previously reported that the albumin content of kidney lysosomal proteins was increased more than ten-fold in nephrotic rats compared to control rats, suggesting that kidney lysosomes play an important role in protein degradation in NS. The present study was carried out to elucidate the role of catabolism of BNP, which is one of the functional protein-natriuretic peptides. We injected puromysin aminonucleoside(PAN) to induce the nephrotic rat state and isolated kidney lysosomes from normal and nephrotic rat kidney cortex by our methods. Immunoblot analysis of tricine-SDS polyacrylamide gel electrophoresis of rat kidney lysosomal proteins revealed the presence of an immuno-reactive peptide band, corresponding to the endogenous BNP. In addition, this was reduced as compared with the normal control. These result suggest that kidney lysosomes play an important role in BNP metabolism to maintain body fluid homeostasis and regulate blood pressure levels.

The study on the relationship between serum vascular endothelial growth factor and proteinuria in adriamycin-induced nephrotic rats.

To study the relationship between serum vascular endothelial growth factor (VEGF) and proteinuria in adriamycin-induced nephrotic rats, a rat model of adriamycin-induced nephrotitis was developed by injection of adriamycin into a tail vein in a rat. At different time points, 24-h urinary protein excretion was measured by using Coomassie brilliant blue method and the serum VEGF levels detected by using ELISA assay. The interventional effect of VEGF on this model was observed. The results showed that: (1) The adriamycin-induced nephrotic syndrome rat model was developed successfully; (2) Serum VEGF levels and proteinuria were significantly increased at 7th day after intravenous injection of adriamycin. There was a positive correlation between serum VEGF levels and 24-h urinary protein excretion (r = 0.67, P < 0.05). (3) The 24-h urinary protein excretion was significantly increased in the rats receiving administration of VEGF (P < 0.05). It was concluded that VEGF might play an important role in the pathogenesis of proteinuria in adriamycin-induced nephrotic rats.

Increased synthesis and avp unresponsiveness of Na,K-ATPase in collecting duct from nephrotic rats.

Renal sodium retention is responsible for ascites and edema in nephrotic syndrome. In puromycin aminonucleoside (PAN)-induced nephrosis, sodium retention originates in part from the collecting duct, and it is associated with increased Na,K-ATPase activity in the cortical collecting duct (CCD). The aims of this study were to evaluate whether the outer medullary collecting duct (OMCD) also participates to sodium retention and to determine the mechanisms responsible for stimulation of Na,K-ATPase in CCD. PAN nephrosis increased Na,K-ATPase activity in the CCD but not in OMCD. The two-fold increase of Na,K-ATPase activity in CCD was associated with two-fold increases in the number of alpha and beta Na,K-ATPase subunits mRNA determined by quantitative RT-PCR and of the total amount of Na,K-ATPase alpha subunits estimated by Western blotting. PAN nephrosis also increased two-fold the amount of Na,K-ATPase alpha subunit at the basolateral membrane of CCD principal cells, as determined by Western blotting after biotinylation and streptavidin precipitation and by immunofluorescence. The intracellular pool of latent Na,K-ATPase units also increased in size and was no longer recruitable by vasopressin and cAMP. This unresponsiveness of the intracellular pool of Na,K-ATPase to vasopressin was not the result of any alteration of the molecular and functional expression of the vasopressin V(2) receptor/adenylyl cyclase (AC) complex. It is concluded that PAN nephrosis (1) does not alter sodium reabsorption in OMCD, (2) is associated with increased synthesis and membrane expression of Na,K-ATPase in the CCD, and (3) alters the normal trafficking of intracellular Na,K-ATPase units to the basolateral membrane.

Glomerular injury and tubular loss in adriamycin nephrosis.

Glomerular injury manifested by sustained proteinuria usually leads to tubule injury and reduction of the GFR. The current study explored the link between these processes in rats with adriamycin nephrosis. One group of nephrotic rats received a vasopressin V2 receptor blocker (V2X) from 4 to 16 wk after injection of adriamycin, whereas a second group received no treatment (NoRx). V2 receptor blockade increased urine volume without affecting protein excretion. At 16 wk, both groups of nephrotic rats exhibited a marked reduction in GFR in comparison with normal controls (V2X, 0.22 +/- 0.19 ml/min; NoRx, 0.20 +/- 0.11 ml/min; control, 1.23 +/- 0.11 ml/min). Morphologic studies revealed that the majority of glomeruli in nephrotic rats were no longer connected to normal tubule segments (V2X, 81 +/- 21%; NoRx, 85 +/- 18%; control, 1 +/- 2%). Glomeruli without tubules were not, however, globally sclerosed. Disruption of the glomerular tubular junction was associated with the presence of amorphous material separating damaged tubule cells from the basement membrane. Serial sections revealed that this material spread from extensive areas of adhesion between the glomerular tuft and capsule to invest the tubular neck. Reduction of the GFR was strongly correlated with the fraction of glomeruli not connected to normal tubules (r(2) = 0.82; P < 0.0001). V2 receptor blockade did not preserve renal function or structure. These findings suggest that local extension of glomerular injury to destroy the tubule neck is an important cause of loss of renal function in adriamycin nephrosis.

Collecting duct is a site of sodium retention in PAN nephrosis: a rationale for amiloride therapy.

Micropuncture studies of the distal nephron and measurements of Na,K-ATPase activity in microdissected collecting tubules have suggested that renal retention of sodium in puromycin aminonucleoside (PAN) nephrotic rats originates in the collecting duct. The present study demonstrated this hypothesis by in vitro microperfusion and showed that amiloride was able to restore sodium balance. Indeed, isolated perfused cortical collecting ducts from PAN-treated rats exhibited an abnormally high transepithelial sodium reabsorption that was abolished by amiloride, and in vivo administration of amiloride fully prevented decreased urinary sodium excretion and positive sodium balance in nephrotic rats. As expected from the aldosterone independence of Na(+) retention in PAN nephrotic rats, blockade of aldosterone receptor by potassium canrenoate did not alter urinary Na(+) excretion, Na(+) balance, or ascites formation in PAN nephrotic rats.

EARLY ADMINISTRATION OF PDTC IN ADRIAMYCIN NEPHROPATHY: EFFECT ON PROTEINURIA, CORTICAL TUBULOINTERSTITIAL INJURY, AND NF- B ACTIVATION

The persistence of NF-κB independent inflammatory signals in the cortical tubulointerstitium may explain the incomplete suppression of interstitial monocyte accumulation by the antioxidant NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), in nephrotic rats with established Adriamycin nephropathy (AN). Because PDTC is known to have anti-proteinuric effects, in this study we investigated whether earlier commencement, during the pre-nephrotic phase of AN, would be more effective in reducing interstitial monocyte accumulation. Male Wistar rats with AN received either vehicle or PDTC (50 mg/kg bd i.p.i.) from d7 until d30 (n = 8 per group). On d30, PDTC reduced renal cortical lipid peroxidation (43%), wet kidney weight and tubulointerstitial injury in AN, but did not decrease proteinuria. Accordingly, inhibition of interstitial ED-1 accumulation remained incomplete (52%). Interestingly, the early administration of PDTC in AN, induced polyuria and renal cortical NF-κB DNA-binding activity was reduced by only 35%. These results suggest that: (i) the combination of an anti-proteinuric agent with PDTC may be required to completely suppress interstitial monocyte cell accumulation in AN and, (ii) the timing and duration of PDTC therapy are an important determinant of its efficacy to reduce NF-κB activation, in vivo.

LDL size and susceptibility to oxidation in experimental nephrosis.

The aim of this study was to investigate the relationship between endothelial dysfunction and low density lipoprotein (LDL) size and susceptibility to oxidation in nephrotic rats with or without deficiency of vitamin E and selenium. Four groups of male Wistar rats were studied: control (C), vitamin E and selenium deficient control (DefC), nephrotic (NS), and vitamin E and selenium deficient NS (DefNS). Nephrotic syndrome was induced by puromycin aminonucleoside. The molar ratio of vitamin E/LDL-cholesterol was significantly lower in DefNS, DefC rats, and NS vs. C rats. In comparison with control animals, vasodilation and LDL oxidability were significantly lower in nephrotic animals. LDL size was similar in all groups. Abnormal endothelial function in response to acetylcholine and carbachol was observed in NS animals compared to control rats. Relaxation response was inversely associated with an increase in LDL susceptibility to oxidation and with a lower molar ratio of vitamin E/LDL-c. LDL oxidability and LDL-c were the only variables independently associated with vasodilation. These results suggest that endothelial dysfunction of NS may be a consequence of the increased LDL susceptibility to oxidation, secondary to antioxidant deficiency.

Fertility diminution in female rats with experimental chronic nephrosis.

Chronic aminonucleoside nephrosis in rats is an experimental analogue of human focal segmental glomerulosclerosis. This study was undertaken to define the effects of chronic nephrosis on the pituitary-ovarian axis and on fertility. Chronic nephrosis was induced by puromycin aminonucleoside and followed for 112 days. The estrous cycle was evaluated daily in all rats, whereas biochemical parameters, hormonal concentrations, and fertility were measured on Days 7, 14, 28, 56, 84, and 112 (n = 8). Animals were divided in four experimental groups: A, B, C, and D. Group A was used to determine LH, FSH, progesterone, and estradiol concentrations. Group B was used to evaluate fertility, and groups C and D were added to clarify the role of male rats in the fertility of nephrotic female rats. The results showed a persistent proteinuria in nephrotic rats; the estrous cycle of nephrotic animals was disrupted. The LH and estradiol concentrations were significantly low at all time points evaluated, whereas no significant changes were noted in FSH or progesterone values. In addition, fertility and litter size were diminished in nephrotic female rats. Interestingly, the presence of a male rat or its urine resulted in a positive influence on serum estradiol concentrations of nephrotic female rats. These data indicate that experimental chronic nephrosis results in a pituitary-ovarian dysfunction that is characterized by low LH concentration, hypoestrogenism, failure of the hormonal feedback control, and diminution of fertility. In addition, they show the positive effect of a male rat on the fertility of a nephrotic female, which strongly suggests the participation of pheromones.

Glomerular function and morphology in puromycin aminonucleoside nephropathy in rats.

The most characteristic manifestation of minimal-change nephropathy is podocyte cell process broadening. In a previous study in children from our unit, we found an inverse correlation between foot process width, glomerular filtration rate (GFR), and filtration fraction. The aim of the present study was to determine whether this relationship also existed in the puromycin aminonucleoside (PAN) experimental model. Sixteen Munich-Wistar-Frömter male rats initially weighing median 247 g (range 171-286) were used. Four rats served as controls. The other 12 rats were divided into three groups receiving daily subcutaneous injections of 1, 1.67, and 2.5 mg PAN/100 g body weight respectively, for 6 days. GFR was determined by clearance of inulin and the fractional urine albumin excretion was measured. Standard stereological methods were used to estimate the glomerular volume, the mean foot process width and the length density of slit pores. GFR decreased with increasing PAN doses. The glomerular volume was increased in the group receiving the lowest PAN dose, while it was decreased in the group with the highest PAN dose, compared with controls. The fractional albumin excretion and the foot process width increased and the total slit pore length decreased with increasing doses of PAN. GFR correlated directly with the glomerular volume as did the foot process width with the fractional albumin excretion. The foot process width correlated inversely with the glomerular volume as did the glomerular volume with the fractional albumin excretion, and GFR with foot process width. The decreased GFR found in the nephrotic rats was inversely related to foot process width and directly related to glomerular volume, confirming our previous results in children in an early stage of the nephrotic syndrome.

Severe proteinuria, sustained for 6 months, induces tubular epithelial cell injury and cell infiltration in rats but not progressive interstitial fibrosis.

Sustained proteinuria is reported to be very harmful to the tubulointerstitium, leading to severe interstitial injury. However, it remains unclear whether sustained proteinuria itself is responsible for severe interstitial injury because, in the previously reported models, the development of factors other than proteinuria in tubulointerstitial lesions could not be excluded completely. After treatment to induce immune tolerance to mouse immunoglobulin, 20 rats were injected with anti-rat slit diaphragm monoclonal antibody (mAb) 5-1-6 twice a week for 6 months and were then sacrificed. mAb 5-1-6 induced massive proteinuria in 11 rats. In nine rats with mild proteinuria, no histological alteration could be detected with light microscopy and immunofluorescence. In nephrotic rats, light microscopy showed minor glomerular abnormalities, with interstitial oedema, tubular epithelial cell degeneration and interstitial cell infiltration. Immunofluorescence revealed increased expression of vimentin and an increased number of OX1-, OX19- and ED1-positive cells. However, we could not detect any accumulation of type I and IV collagen or laminin in the tubulointerstitium. RT-PCR showed that the expression of mRNA for type I collagen was not increased, compared with that in control rats. We succeeded in developing a model of persistent nephrosis without severe glomerular abnormalities, nephrectomy or other manoeuvres known to induce disturbed haemodynamics, using an agent without tubulointerstitial toxicity, and considered it to be suitable for investigating the direct toxicity of proteinuria. In this model, isolated massive proteinuria induced interstitial injury. However, the degree of injury was suggested to be much less than that observed in other previously developed models.

Effect of the lipoprotein lipase activator NO-1886 on adriamycin-induced nephrotic syndrome in rats

Hyperlipidemia associated with nephrotic syndrome may play a role in the deterioration of renal function. Tsutsumi et al have previously reported that the novel compound NO-1886 increases lipoprotein lipase (LPL) activity, resulting in a reduction of plasma triglycerides and an elevation of high-density lipoprotein (HDL) cholesterol in normal rats. The aim of this study was to ascertain whether NO-1886 suppresses the renal injury by treatment of the hyperlipidemia in an Adriamycin (Kyowa Hakko Kogyo, Tokyo, Japan) induced nephrosis rat model fed a high-protein diet that induced renal dysfunction and tubulointerstitial injury. Administration of Adriamycin caused hyperlipidemia, proteinuria, and edema with ascites in rats in 4 weeks. Furthermore, a combination of Adriamycin and a high-protein diet increased plasma creatinine and blood urea nitrogen (BUN) and decreased plasma albumin. Histologically, in Adriamycin-treated rats, marked interstitial cellular infiltration, tubular lumen dilation, and tubular cast formation in the kidney were observed. NO-1886 decreased plasma triglyceride and increased HDL cholesterol in Adriamycin-induced nephrotic rats. NO-1886 treatment reduced plasma creatinine and BUN levels and increased plasma albumin in Adriamycin-treated rats; it also ameliorated the ascites and proteinuria. Histologically, NO-1886-treated rats showed a quantitatively significant preservation of tubulointerstitial lesions. These data suggest that NO-1886 may have a protective effect against Adriamycin-induced nephrosis with tubulointerstitial nephritis in rats by a modification of the plasma lipid disorder.

Tissue distribution of alpha-tocopherol in nephrotic rats.

1. Reactive oxygen species are involved in the pathogenesis of puromycin aminonucleoside (PAN) nephrosis and alpha-tocopherol is one of the major anti-oxidants in the body. 2. In the present study, we measured the levels of alpha-tocopherol by high-performance liquid chromatography in the plasma and in nine tissues of control and nephrotic rats obtained 10 days after either 0.9% saline solution or PAN injection, respectively. 3. In nephrotic rats, alpha-tocopherol levels increased four-fold in plasma; however, the molar ratio of alpha-tocopherol/ cholesterol remained unchanged, suggesting that the increase in alpha-tocopherol content was attributable to an increase in plasma lipid concentration. 4. In nephrotic rats, the alpha-tocopherol/cholesterol ratio increased 1.33-fold in adrenal glands and 1.34-fold in the testis, but remained unchanged in heart, spleen, liver, kidney lung, brain and muscle. 5. These data suggest that, in PAN nephrotic rats, there are alterations in the distribution of alpha-tocopherol and there is no deficiency of alpha-tocopherol in plasma or tissues.

Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes.

In puromycin aminonucleoside (PAN)-treated nephrotic rats, sodium retention is associated with increased (Na+/K+)-ATPase activity in the cortical collecting ducts (CCD). This study was undertaken to determine whether stimulation of (Na+/K+)-ATPase in the CCD is a feature of other experimental nephrotic syndromes, whether it might be responsible for renal sodium retention, and whether it is mediated by increased plasma vasopressin levels or activation of calcineurin. For this purpose, the time courses of urinary excretion of sodium and protein, sodium balance, ascites, and (Na+/K+)-ATPase activities in microdissected CCD were studied in rats with PAN or adriamycin nephrosis or HgCl2 nephropathy. The roles of vasopressin and calcineurin in PAN nephrosis were evaluated by measuring these parameters in Brattleboro rats and in rats treated with cyclosporin or tacrolimus. Despite different patterns of changes in urinary sodium and protein excretion in the three nephrotic syndrome models, there was a linear relationship between CCD (Na+/K+)-ATPase activities and sodium excretion in all three cases. The results also indicated that there was no correlation between proteinuria and sodium retention, but ascites was present only when proteinuria was associated with marked reduction of sodium excretion. Finally, the lack of vasopressin in Brattleboro rats or the inhibition of calcineurin by administration of either cyclosporin or tacrolimus did not prevent development of the nephrotic syndrome in PAN-treated rats or stimulation of CCD (Na+/K+)-ATPase. It is concluded that stimulation of Na(+/K+)-ATPase in the CCD of nephrotic rats might be responsible for sodium retention and that this phenomenon is independent of proteinuria and vasopressin and calcineurin activities.

Effect of astragalus- angelica mixture on lipoprotein lipase and lecithin- cholesterol acyltransferase of nephrotic rats

To investigate the mechanism of Astragalus Angelica Mixture (AAM) effect of regulating lipid metabolism disturbance in nephrotic rats. To examine the effects of AAM on serum albumin, lipid levels, and activities of lipoprotein lipase (LPL) and lecithin-cholesterol acyltransferase (LCAT), which are key enzymes for catabolism of lipid, in immune-induced nephrotic hyperlipidemia rats and exogenous hyperlipidemia rats. Serum albumin was reduced, lipid increased significantly, LPL activity decreased significantly and the LCAT activity was relatively insufficient in nephrotic rats. Activities of LPL and LCAT increased significantly in AAM treated nephrotic rats. There were no change of activities of LPL and LCAT in exogenous hyperlipidemia rats and AAM showed no effect on the activities of these two enzymes. The effect of AAM in regulating lipid metabolism might be due to enhancing the clearance of triglyceride and cholesterol-rich lipoprotein by improving the activities of LPL and LCAT.

Renal protective effects of blocking the intrarenal renin-angiotensin system: angiotensin II type I receptor antagonist compared with angiotensin-converting enzyme inhibitor.

The present study compared renoprotective effects of angiotensin II type I receptor antagonist (AT1RA) with angiotensin converting enzyme inhibitor (ACEI), and their influence on the renin-angiotensin-system (RAS). Experimental nephrotic syndrome was induced in SD rats by repeated peritoneal injections of puromycin. Twenty-eight rats were randomly divided into four groups: normal control, nephrotic control, ACEI-treated, and AT1RA-treated groups. Serum, urine, and renal tissue were collected for study at the end of 12 weeks. Compared with those of the nephrotic control group, urinary protein was less and renal function was better in both treated groups. The glomerular and interstitial damage indexes of both ACEI- and AT1RA-treated rats were lower than those of nephrotic control rats, with no significant difference observed between the two treated groups. Local renal ACE activity and angiotensin II concentration were elevated in nephrotic rats (p< 0.01). However, there is no significant difference in circulating RAS, renal tissue renin, and aldosterone between the normal control and nephrotic control rats. As expected, enalapril inhibited the local renal ACE activity and significantly decreased angiotensin II (p< 0.01). Intrarenal ACE activity and angiotensin concentration returned to normal levels after treatment with irbesartan (p< 0.01). In conclusion, AT1RA and ACEI have comparable renal protective effects, and these protective effects were associated with the inhibition of intrarenal ANG II.

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