Dietary soy protein effects on inherited polycystic kidney disease are influenced by gender and protein level

The effects of dietary soy protein compared to casein were examined in male and female CD1-pcy/pcy (pcy) mice with polycystic kidney disease. Animals 10 wk of age were fed purified diets containing either soy protein isolate or casein given at a level of 17.4 or 6% protein. After 13 wk on the diets, body weights and serum concentrations of albumin and protein indicated that protein nutrition was adequate on all diets. Overall, animals fed soy protein versus casein had 28% lower (P = 0.0037) relative kidney weights (g/100 g body wt), 37% lower (P = 0.0089) cyst scores (% cyst area x relative kidney weight), and 25% less (P = 0.0144) kidney water (g). Dietary protein reduction resulted in 30% lower (P = 0.0010) relative kidney weights, 25% lower (P = 0.0327) cyst scores, and 35% less (P = 0.0001) kidney water. Analysis of interactions between main effects revealed that the effects of soy protein on kidney size were significant only in females, and that effects of soy protein on cyst score were significant only in animals on the low protein diets. In addition, differences in kidney weights and cyst score due to protein reduction were significant in animals fed soy protein, but not in those fed casein as the protein source. These results show that both dietary protein source and level significantly affect polycystic kidney disease in pcy animals, with the effects of dietary soy protein being most pronounced in female animals fed the low protein diets and the effects of protein reduction being most pronounced in animals fed soy protein-based diets.     

Improved survival of heterotopic cardiac allografts in rats with dietary n-3 polyunsaturated fatty acids

A heterotopic cardiac transplant model, with male Fischer 344 rats as donors and Long Evans rats as recipients, was utilized to investigate the effect of dietary n-3 polyunsaturated fatty acids on acute rejection. Both donor and recipient rats were fed purified diets high in either n-3 polyunsaturated fatty acids (from concentrated n-3 ethyl esters [EE] or fish oil [FO]) or n-6 polyunsaturated fatty acids (from corn oil [CO]) for either 2-3 or 3-4 weeks before transplant. The recipient rats continued on their diets until rejection. The AIN-76A-based diets (with 30% of calories as fat) had adequate essential fatty acids and were balanced for sterols and antioxidants. Allograft survival was significantly increased by 45% when recipient rats were fed EE as compared to the control (CO diet fed to both donor and recipient), regardless of the diet fed to the donor. There was a slight but significant increase in allograft survival when only donor rats were fed the EE diet 2-3 weeks before transplant. With the FO diet (containing one third of the n-3 fatty acids in the EE diet), only the group fed FO to both donor and recipient (starting 2-3 weeks before transplant) showed a significant increase in allograft survival over the control. However, if the FO diets were fed for 3-4 weeks before transplant, increased survival was seen in groups fed FO to either the donor or recipient alone. In this case, allograft survival with FO feeding to both donor and recipient was not different from recipient treatment alone. In all the studies there was a significant and direct correlation between allograft survival and the donor heart phospholipid n-3/n-6 fatty acid ratio and the n-3 fatty acid content (at rejection). There was an indirect relationship with the n-6 fatty acid content. There was no detectable 20:3 (n-9) in the cardiac phospholipids, indicating the absence of essential fatty acid deficiency. Recipient diets were the strongest determinant of the fatty acid composition in the transplanted donor heart. The data indicate that providing dietary n-3 polyunsaturated fatty acids before and after cardiac transplant to recipient animals provides a significant protection against acute rejection.     

Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice.

The mechanisms of action of dietary fish oil (FO) on osteoporosis are not fully understood. This study showed FO decreased bone loss in ovariectomized mice because of inhibition of osteoclastogenesis. This finding supports a beneficial effect of FO on the attenuation of osteoporosis. INTRODUCTION: Consumption of fish or n-3 fatty acids protects against cardiovascular and autoimmune disorders. Beneficial effects on bone mineral density have also been reported in rats and humans, but the precise mechanisms involved have not been described. METHODS: Sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO) or 5% fish oil (FO). Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF-kappaB ligand (RANKL) expression and cytokine production in activated T-cells were analyzed by flow cytometry and ELISA, respectively. Osteoclasts were generated by culturing bone marrow (BM) cells with 1,25(OH)2D3. NF-kappaB activation in BM macrophages was measured by an electrophoretic mobility shift assay. RESULTS AND CONCLUSION: Plasma lipid C16:1n6, C20:5n3, and C22:6n3 were significantly increased and C20:4n6 and C18:2n6 decreased in FO-fed mice. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO-fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4+ T-cells from CO-fed OVX mice, but there was no change in FO-fed mice. Selected n-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) added in vitro caused a significant decrease in TRACP activity and TRACP+ multinuclear cell formation from BM cells compared with selected n-6 fatty acids (linoleic acid [LA] and arachidonic acid [AA]). DHA and EPA also inhibited BM macrophage NF-kappaB activation induced by RANKL in vitro. TNF-alpha, interleukin (IL)-2, and interferon (IFN)-gamma concentrations from both sham and OVX FO-fed mice were decreased in the culture medium of splenocytes, and interleukin-6 was decreased in sham-operated FO-fed mice. In conclusion, inhibition of osteoclast generation and activation may be one of the mechanisms by which dietary n-3 fatty acids reduce bone loss in OVX mice.     

Fatty acid intake and Kupffer cell function: fish oil alters eicosanoid and monokine production to endotoxin stimulation

Diets high in n-3 fatty acids appear to have an anti-inflammatory effect, which is thought to be due to decreased macrophage prostaglandin (PG) and thromboxane (Tx) production after incorporation of these fatty acids into cell membrane phospholipids. The effect of n-3 fatty acids incorporation on macrophage monokine release in response to septic stimuli is not well established. Kupffer cells, the fixed macrophages of the liver, were obtained from rats fed diets with fat sources derived from corn oil (CO, control), fish oil (FO, high in n-3 fatty acids), or safflower oil (SO, high in n-6 fatty acids) for 2 or 6 weeks. After exposure to bacterial lipopolysaccharide, Kupffer cells from rats fed FO for 2 or 6 weeks produced less PG and Tx than Kupffer cells from rats fed CO or SO. After 2 weeks of defined diets, interleukin-1 (IL-1) and tumor necrosis factor release were not affected by dietary fat source. In contrast, after 6 weeks of feeding, Kupffer cells from both the FO and the SO groups released less IL-1 and tumor necrosis factor when triggered by lipopolysaccharide than Kupffer's cells from animals fed the control diet that contained CO. These data suggest that altered monokine release from macrophages may contribute to the anti-inflammatory effect of diets high in n-3 fatty acids. Also shown in our results is that prolonged changes in membrane phospholipid content induced by dietary fat source can influence not only PG and Tx production but monokine release as well.     

Elevated bone turnover in rat polycystic kidney disease is not due to prostaglandin E2

Hyperparathyroidism, secondary to renal disease, is thought to cause high bone turnover via prostaglandin E2 (PGE2). Diets high in n-3 fatty acids reduced PGE2. Thus the objective was to compare the effect of diets high in n-6 and n-3 fatty acids on hyperparathyroidism, bone turnover, and PGE2 in Han:SPRD- cy rats that develop polycystic kidney disease (PKD). Weanling male rats ( n=58) were randomized to diets made with either corn or flaxseed oil (5%) for 8 weeks, followed by measurement of plasma parathyroid hormone (PTH), osteocalcin, urinary N-telopeptide (NTX), and ex vivo release of PGE2from femur. Plasma PTH was elevated ( P<0.01) as a result of PKD. Mean values for plasma osteocalcin and urinary NTX were elevated ( P<0.01) by PKD but not altered by diet. In contrast, values for PGE2 were lowest in the PKD rats fed flaxseed oil compared with PKD rats fed corn oil and compared with non-affected rats fed either oil. Rats with PKD have high-turnover bone disease, likely due to hyperparathyroidism, that is unaffected by feeding corn or flaxseed oils. Since PGE2 release is lower in the presence of high bone turnover, the high bone turnover in evolving rat uremia is not likely to be mediated by PGE2.     

Evidence that soyasaponin Bb retards disease progression in a murine model of polycystic kidney disease

BACKGROUND: We reported a lessened cyst growth in the pcy mouse model of polycystic kidney disease (PKD) when mice were fed a soy protein isolate (SPI)-based diet and hypothesized that the soyasaponins may be associated with this therapeutic effect. The effects of feeding a saponin-enriched alcohol extract (SEAE) from SPI, an isoflavone- and saponin-enriched soy supplement (Novasoy 400), or a 99.5% pure soyasaponin Bb powder on cyst growth are reported here. METHODS: The therapeutic effects of the soyasaponins were studied in 60-day-old male pcy mice in two separate, 90-day feeding trials. In the first study, mice were fed either a casein-based (control) diet, a diet in which SPI replaced the casein or the control diet supplemented with SEAE. In the second study, mice were fed the control diet unsupplemented or supplemented with either a soyasaponin- and isoflavone-enriched soy product (Novasoy 400) or a 99.5% pure soyasaponin Bb powder. RESULTS: In study 1, kidney weight, water content, and plasma creatinine and urea levels were markedly reduced in the SEAE-fed animals compared to tissues from the control group; likewise, mice fed the SPI-based diet showed a decreased plasma creatinine, but only a slightly reduced plasma urea. In study 2, kidney weight, water content, plasma creatinine and urea levels were significantly reduced in mice fed the soyasaponin Bb powder and the Novasoy-400 supplement, compared to controls. CONCLUSION: Soyasaponin Bb can impede kidney enlargement and cyst growth in the pcy mouse model of PKD. Further studies are needed to determine its most effective dose and mechanism of action.     

Effects of potassium citrate/citric acid intake in a mouse model of polycystic kidney disease

The kidney function in a model of autosomal dominant polycystic kidney disease (PKD), the Han:SPRD rat, is dramatically improved by chronic ingestion of a solution of potassium citrate and citric acid (KCitr). This study investigated whether this treatment would also be beneficial in the pcy/pcy mouse, a model of autosomal recessive PKD. Starting at 1 month of age, male CD-1 pcy/pcy and normal CD-1 mice were provided with a solution of 55 mM K(3) citrate/67 mM citric acid or tap water to drink. The pcy/pcy mice on the KCitr solution failed to grow normally and showed elevated plasma urea levels when compared to water-drinking littermates. Growth of normal CD-1 mice was not affected by KCitr intake. The pcy/pcy mice were then provided with a more dilute solution of KCitr to drink: this resulted in greater kidney wet and dry weights and a higher kidney weight/body weight ratio, but no beneficial effects. We conclude that pcy/pcy mice cannot tolerate a high level of KCitr intake and that a lower level is of no benefit. Whether KCitr therapy would be helpful in patients with PKD is still an open question.     

Dietary soy protein effects on disease and IGF-I in male and female Han:SPRD-cy rats

BACKGROUND: Dietary soy protein compared with casein retards disease progression in a gender-specific manner in the pcy mouse. In this model of polycystic kidney disease (PKD), kidney insulin-like growth factor-I (IGF-I) levels are elevated. The present study examined the gender-specific effects of soy protein feeding on disease and IGF-I in Han:SPRD-cy rats. METHODS: Normal (+/+) and affected (cy/+) weanling male and female Han:SPRD-cy rats were given either casein- or soy protein-based diets for six weeks. Renal size, water content, cyst size and IGF-I, serum creatinine, urea and IGF-I, and creatinine clearance were determined. RESULTS: Soy protein-fed cy/+ animals had lower kidney weight, water content and cyst size, lower serum urea and creatinine, and higher creatinine clearance. In cy/+ females, dietary soy protein resulted in normalized serum creatinine and creatinine clearance. Kidney IGF-I levels (ng/kidney) were 32 to 76% higher in cy/+ compared with +/+ groups (P < 0.001). Soy protein feeding resulted in lower kidney IGF-I in cy/+ males (1123 vs. 1496 ng/kidney, P < 0.001) and cy/+ females (816 vs. 943 ng/kidney, P < 0.05). In males, soy protein feeding resulted in lower serum IGF-I concentrations in +/+ (1439 vs. 1708 ng/mL, P < 0.05) and in cy/+ (1483 vs. 2073 ng/mL, P < 0.001) animals. CONCLUSIONS: Dietary soy protein compared with casein delays the progression of disease in male and female Han:SPRD-cy rats. Overall, IGF-I was lower in +/+ animals, in females, and in animals consuming the soy protein diet, supporting a role for IGF-I in the pathogenesis of disease in the Han:SPRD-cy rat and an ameliorating role for dietary soy protein.     

Low-protein diet suppresses serum insulin-like growth factor-1 and decelerates the progression of growth hormone-induced glomerulosclerosis

A low-protein (LP) diet has been associated with amelioration of renal function in glomerulosclerosis (GS). However, the mechanisms involved are still unclear. We have used a mouse transgenic for bovine growth hormone (GH), which develops progressive GS and exhibits consistently elevated levels of circulating GH and insulin-like growth factor (IGF)-1, to study the effect of dietary protein restriction. LP (6% protein) and normal-protein (NP, 20% protein) diets were maintained for 30 weeks in mice with established GS of mild/moderate degree. The degree of GS was markedly attenuated in LP compared to NP mice. Quantitative analysis revealed a significantly lower GS index (1.4 +/- 0.9 in LP vs. 2.8 +/- 0.8 in NP) and glomerular volume (0.8 x 10(6) +/- 0.1 x 10(6) microm(3) in LP vs. 1.2 x 10(6) +/- 0.1 x 10(6) microm(3) in NP) in mice with restricted protein intake. These morphologic changes were accompanied by a significant reduction in renal expression of alpha(1) type-IV collagen (2.4-fold) and tenascin (1.4-fold) in LP mice. Serum IGF-1 decreased by 40% and showed a significant correlation with alpha(1) type-IV collagen expression with the LP diet. The present finding supports the use of the LP diet to decelerate the progression of GS and furthermore suggests that one of the mechanisms involved in this process is the GH/IGF-1 regulation by protein intake.     

Effect of dietary soy protein and genistein on disease progression in mice with polycystic kidney disease

The effects of feeding a soy protein isolate or genistein, an isoflavonoid present in soy protein, on cyst development were examined in the DBA/2FG-pcy (pcy) mouse, an accepted animal model of polycystic kidney disease, before the appearance of clinical symptoms. In study 1, 60-day-old male pcy mice were evenly divided into two groups and fed semipurified diets, based on casein or a soy protein isolate (15 g protein/100 g diet) for 90 days. In study 2, the animals were fed a casein-based diet (25 g casein/100 g diet) with or without genistein (0.05 g/100 g diet) for 60 days. In study 1, total kidney weight and kidney weight relative to body weight were significantly reduced (by 24% to 25%) in the animals fed the soy protein-based diet, relative to the casein-fed group, as was kidney water content (by 38%). In addition, mean cyst volume, as measured by morphometry, were lower (by 25%) in kidneys from the soy protein-fed group. No differences were found between these two groups with respect to final body weight, plasma creatinine, and protein content; however, plasma urea values were significantly lower in the soy protein-fed animals. Genistein supplementation of a casein-based diet in study 2 did not reduce the renal enlargement and cyst development associated with progression of polycystic kidney disease. These results suggest that soy protein is effective in retarding cyst development in the pcy mouse and that this beneficial effect may be unrelated to its genistein content.     

Dietary Protein as a Risk Factor in Gentamicin Nephrotoxicity

The effects of dietary protein on renal function and structure, both prior to and after initiation of daily gentamicin treatment, were investigated. Male Sprague-Dawley rats were pair-fed on low-protein (LP, 5%), normal-protein (NP, 20%), or high-protein (HP, 60%) diets for 10 days prior to gentamicin treatment. Gentamicin was administered as daily subcutaneous injections (150 mg/kg) for 6 days. Immediately after beginning daily gentamicin injections some of the rats on NP diets were switched to LP or HP diets, and some of the rats on HP diets were switched to LP diets. Renal function was monitored by evaluating serum creatinine levels and 24-h urine volumes; renal histology was evaluated by light and electron microscopy; and gentamicin uptake was determined using radioimmunoassay. Our findings indicate that conditioning to higher dietary protein prior to gentamicin administration results in less uptake of gentamicin by the kidneys. If rats on HP diets are placed on LP coincident with gentamicin administration, there is a significant improvement in survival. Switching rats from NP to LP protein coincident with gentamicin administration does not improve renal function, histology, or survival. However, switching rats from NP to HP coincident with gentamicin administration significantly increases mortality. Maintaining rats on LP both prior to and after gentamicin administration results in a significant improvement in survival but does not improve renal Junction. These results indicate that dietary protein both prior to and following the administration of gentamicin can significantly affect the nephrotoxicity of gentamicin.     

Dietary protein as a risk factor in gentamicin nephrotoxicity

The effects of dietary protein on renal function and structure, both prior to and after initiation of daily gentamicin treatment, were investigated. Male Sprague-Dawley rats were pair-fed on low-protein (LP, 5%), normal-protein (NP, 20%), or high-protein (HP, 60%) diets for 10 days prior to gentamicin treatment. Gentamicin was administered as daily subcutaneous injections (150 mg/kg) for 6 days. Immediately after beginning daily gentamicin injections some of the rats on NP diets were switched to LP or HP diets, and some of the rats on HP diets were switched to LP diets. Renal function was monitored by evaluating serum creatinine levels and 24-h urine volumes; renal histology was evaluated by light and electron microscopy; and gentamicin uptake was determined using radioimmunoassay. Our findings indicate that conditioning to higher dietary protein prior to gentamicin administration results in less uptake of gentamicin by the kidneys. If rats on HP diets are placed on LP coincident with gentamicin administration, there is a significant improvement in survival. Switching rats from NP to LP protein coincident with gentamicin administration does not improve renal function, histology, or survival. However, switching rats from NP to HP coincident with gentamicin administration significantly increases mortality. Maintaining rats on LP both prior to and after gentamicin administration results in a significant improvement in survival but does not improve renal function. These results indicate that dietary protein both prior to and following the administration of gentamicin can significantly affect the nephrotoxicity of gentamicin.     

Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.     

Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease

Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTR(inh)-172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation. These compounds also inhibited cyst number and growth by >80% in an embryonic kidney cyst model involving 4-d organ culture of embryonic day 13.5 mouse kidneys in 8-Br-cAMP-containing medium. Subcutaneous delivery of tetrazolo-CFTR(inh)-172 and Ph-GlyH-101 to neonatal, kidney-specific PKD1 knockout mice produced stable, therapeutic inhibitor concentrations of >3 microM in urine and kidney tissue. Treatment of mice for up to 7 d remarkably slowed kidney enlargement and cyst expansion and preserved renal function. These results implicate CFTR in renal cyst growth and suggest that CFTR inhibitors may hold therapeutic potential to reduce cyst growth in PKD.     

Plasma and erythrocyte phospholipid fatty acids composition in Serbian hemodialyzed patients

Dyslipidemia is one of the possible risk factors for advanced atherosclerosis in patients with chronic renal failure. Abnormal phospholipid metabolism may play an important role in the progression of atherosclerosis in patients with renal failure. The aim of this study was to determine specific characteristics of plasma and erythrocyte phospholipid content and fatty acid composition in 37 patients with chronic renal failure on hemodialysis (HD). The results were compared with the characteristics of healthy subjects. Briefly, plasma triglyceride (p < 0.001), total cholesterol (p < 0.05), and total phospholipids (p < 0.01) levels were significantly higher and HDL-cholesterol level significantly lower (p < 0.01) in HD patients. Plasma phosphatidylcholine and phosphatidylethanolamine concentration were significantly higher (p < 0.001) in HD patients. The plasma phospholipid fatty acids composition indicated significantly (p < 0.01) higher level of oleic (18:1 n-9) and lower levels of eicopentaenoic (20:5 n-3 EPA) and docosahexaenoic (22:6 n-3 DHA) acids (p < 0.05). However, in HD patients, the relative concentration of plasma phospholipid n-6 polyunsaturated fatty acid (PUFA) was significantly lower (p < 0.05). The fatty acid composition of erythrocyte phospholipid in HD patients was modified with EPA and DHA levels significantly lowered (p < 0.05). Our results demonstrate an abnormal phospholipid metabolism and deficiency of n-3 PUFA in plasma and erythrocyte phospholipids in hemodialyzed patients.     

Rapamycin‐mediated suppression of renal cyst expansion in del34 Pkd1−/− mutant mouse embryos: An investigation of the feasibility of renal cyst prevention in the foetus

Aim: Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end‐stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice. Methods: Pregnant Pkd1^+/? female mice (mated with Pkd1^+/? male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2. Results: Numerous cysts were present in Pkd1^?/? kidneys, which were twice the weight of wild‐type kidneys. Cyst size was reduced by a third in rapamycin‐treated Pkd1^?/? kidney sections and kidney mass was reduced to near wild‐type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin‐treated mice but some lethality was observed in Pkd1^?/? null embryos. Conclusion: Rapamycin treatment reduces cyst formation in Pkd1^?/? mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin‐associated lethality limits its usefulness as a treatment in utero.     

Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human kidney disease and is caused by germline mutations in PKD1 (85%) or PKD2 (15%). It has been estimated that around 1% of tubular cells give rise to cysts, and cell hyperproliferation has been noted to be a cardinal feature of cystic epithelium. Nevertheless, it is uncertain whether the increase in proliferative index observed is an early or late feature of the cystic ADPKD kidney. METHODS: Two Pkd2 mouse mutants (WS25 and WS183) have been recently generated as orthologous models of PKD2. To determine the effect of Pkd2 dosage on cell proliferation, cyst formation and renal fibrosis, we studied renal tissue from Pkd2(WS25/WS25) and Pkd2(+/-) mice by histological analysis. We also examined the proliferative index in archival nephrectomy tissue obtained from patients with ADPKD and normal controls. RESULTS: The proliferative index of non-cystic tubules in Pkd2 mutant mice as assessed by proliferating cell nuclear antigen and Ki67-positive nuclei was between 1-2%, values 5-10 times higher than control tissue. Similarly, the proliferative index of non-cystic tubules in human ADPKD kidneys was 40 times higher than corresponding controls. In Pkd2 mutant mice, significant correlations were found between the fibrosis score and the mean cyst area as well as with the proliferative index. Of significance, proliferating tubular cells were uniformly positive for polycystin-2 expression in Pkd2(+/-) kidney. CONCLUSION: These results suggest that an increase in cell proliferation is an early event preceding cyst formation and can result from haploinsufficiency at Pkd2. The possible pathogenic link between tubular cell proliferation, interstitial fibrosis and cyst formation is discussed.     

Supplementation with n-3 and n-6 polyunsaturated fatty acids: effects on lipoxygenase activity and clinical symptoms of pruritus in hemodialysis patients.

OBJECTIVE: To investigate the effect of supplementation with different sources of oils rich in long chain fatty acids, ie, fish oil (FO) and safflower oil (SO), on the production of leukotriene B4 (LTB4) by polymorphonuclear leukocytes (PMNLs) in hemodialysis patients and the consequent effects on the symptoms of pruritus. DESIGN: Randomized, prospective, double-blind study for 2 treatment groups. SETTING: Three Medical Center-affiliated units. PATIENTS: Twenty-two patients on maintenance hemodialysis, of both sexes, age > or = 20 years with complaint of dry and/or itchy skin. INTERVENTION: Two groups of patients receiving daily supplements of 6 g ethyl ester of FO or SO for 16 weeks. MAIN OUTCOME MEASURES: Red blood cell (RBC) fatty acid profile, LTB 4 production by PMNLs, and pruritus symptoms at baseline and after supplementation. RESULTS: After supplementation, the FO group had a higher RBC 22:6n3, total n-3 fatty acids, and ratio of total n-3 to total n-6 fatty acids (P < .05) than the SO group. The change in LTB4 production (pg/mL) from baseline to week 16 was 240.7 +/- 200.2 to 29.2 +/- 14.6 in the FO group and from 171.1 +/- 121.7 to 31.9 +/- 14.7 in the SO group. The overall pruritus score change was 16.7 +/- 11.4 to 8.9 +/- 9.2 in the FO group and from 17.5 +/- 8.8 to 13.1 +/- 5.6 in the SO group. FO supplementation did not result in a significant specific effect on LTB4 production by the PMNLs. There was a nonsignificant decrease in the pruritus scores that could be clinically significant and important to patients suffering with this condition. CONCLUSION: Supplementation with FO results in significant incorporation of n-3 fatty acids in the RBCs. Intervention with both FO and SO resulted in a nonsignificant improvement of clinical symptoms of pruritus and a nonsignificant reduction in LTB 4 production by PMNLs in the hemodialysis patients. The percent decrease in total puritus score was greater for the FO group compared with the SO group.     

Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?

Data from animal and human studies suggest that the rate of progression of renal insufficiency can be retarded with careful control of blood pressure, institution of a low-protein diet, and the use of lipid-lowering agents. These therapeutic interventions become important when managing patients with renal insufficiency secondary to autosomal dominant polycystic kidney disease (PKD) and autosomal recessive polycystic kidney disease, in which end-stage renal disease is present in nearly 17,000 individuals per year. Several dietary and pharmacologic intervention strategies including blood pressure control, dietary modification, and the use of antioxidants as well as lipid-lowering agents have been studied in humans and animals with PKD in an effort to slow the rate of renal progression. This article reviews the current understanding of the effectiveness of these conventional therapies, as well as novel therapies that specifically target the mediators of cyst formation in PKD using tyrosine kinase inhibitors and gene therapy in an effort to identify potential strategies for retarding cyst formation and parenchymal injury in PKD. Current pharmacologic and dietary strategies fail to show any consistent benefits in preserving renal function and reducing renal injury in human PKD. The therapeutic potential for exciting new gene therapies and pharmacologic agents designed to target the pathophysiologic pathways involved in cyst formation are promising. Randomized, controlled trials in children and adults with early PKD are necessary to evaluate the effectiveness of these therapeutic interventions.     

Fatty acid composition and arachidonic acid concentrations in alveolar bone of rats fed diets with different lipids

Summary The purpose of the present study was to determine if the type of dietary fat can modify the fatty acid composition and arachidonic acid levels in the alveolar bone phospholipids. Three groups of rats were fed nutritionally adequate semipurified diets containing different lipids: 10% corn oil (control, group 1, rich in n-6 fatty acids); 9% butter + 1% corn oil (experimental, group 11, rich in saturated fatty acids); and 9% ethyl ester concentrate of n-3 fatty acids + 1% corn oil (experimental, group 111, rich in n-3 fatty acids). After 10 weeks of feeding the various diets, rats were killed, maxillae and mandibles were dissected out, and the soft tissue was removed. Bone was frozen in liquid nitrogen and pulverized. Powdered bone was extracted for total lipids, and phospholipids were isolated by column chromatography. The fatty acid composition and arachidonic acid concentrations were determined in total phospholipids after the addition of an internal standard, octadecatetraenoic acid (18: 4n-3), and subsequent gas chromatography. The type of dietary lipids had a profound influence on the fatty acid composition of bone lipids. Arachidonic acid concentrations were significantly lower in total phospholipids of mandibles and maxillae of rats fed the experimental diets than in those fed the control diet. Because arachidonic acid is a precursor of prostaglandin E₂ and leukotriene C₄, a significant reduction in its concentration may result in reduced levels of these eicosanoids in the alveolar bone.Presented in part at the International Association for Dental Research Meeting, Glasgow, Scotland, July 1–4, 1992