Low-fat diets and diets containing n-3 fatty acids (FA) slow the progression of renal injury in the male Han:Sprague-Dawley (SPRD)-cy rat model of polycystic kidney disease. To determine whether these dietary fat effects are similar in females and in another model of renal cystic disease, in this study we used both male and female pcy mice to examine the effects of fat level and type on disease progression. Adult pcy mice were fed 4, 10, or 20 g soybean oil/100 g diet for 130 d in study 1. In study 2, weanling pcy mice were fed high or low levels of fat rich in 18:2n-6 (corn oil, CO), 18:3n-3 (flaxseed oil/CO 4:1 g/g, FO), or 22:6n-3 (algal oil/CO 4:1 g/g, DO) for 8 wk. In adult pcy mice, low- compared with high-fat diets lowered kidney weights (2.4 +/- 0.2 vs. 3.1 +/- 0.2 g/100 g body weight, P = 0.006) and serum urea nitrogen (SUN) (9.6 +/- 0.6 vs. 11.9 +/- 0.6 mmol/L, P = 0.009), whereas in young pcy mice it reduced renal fibrosis volumes (0.44 +/- 0.04 vs. 0.62 +/- 0.04 mL/kg body weight, P < 0.0001). FO feeding in young pcy mice mitigated the detrimental effects of high fat on fibrosis while not altering kidney size, function, and oxidative damage when compared with the CO-fed mice. In contrast, DO- compared with CO-fed mice had higher kidney weights (2.64 +/- 0.07 vs. 2.24 +/- 0.08 g/100 g body weight, P = 0.005), SUN (9.4 +/- 0.57 vs. 7.0 +/- 0.62 mmol/L, P < 0.0001), and cyst volumes (7.9 +/- 0.28 vs. 6.2 +/- 0.30 mL/kg body weight, P < 0.0001) and similar levels of oxidative damage and fibrosis. The FA compositions of the diets were reflected in the kidneys: 18:2n-6, 18:3n-3, and 22:6n-3 were the highest in the CO, FO, and DO diets, respectively. Dietary effects on kidney disease progression were similar in males and females. A low-fat diet slows progression of renal injury in male and female pcy mice, consistent with findings in the male Han:SPRD-cy rat. Dietary fat type also influenced renal injury, with flaxseed oil diets rich in 18:3n-3 slowing early fibrosis progression compared with diets rich in 18:2n-6 or in 22:6n-3.

of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys. Am J Physiol Renal Physiol 290: F897-F904, 2006. First published October 18, 2005 doi:10.1152/ajprenal.00332.2005.-Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley-cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B 2 (TXB2, stable metabolite of TXA2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1␣ (6-keto-PGF1␣, stable metabolite of PGI 2)] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 Ϯ 0.02 vs. 0.45 Ϯ 0.11 ng prostanoids ⅐ min Ϫ1 ⅐ mg protein Ϫ1 (P Ͻ 0.001)] and COX-2 [0.64 Ϯ 0.10 vs. 2.32 Ϯ 0.22 ng prostanoids ⅐ min Ϫ1 ⅐ mg protein Ϫ1 (P Ͻ 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were ϳ2-10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB 2 Ͼ 6-keto-PGF 1␣ Ͼ PGE2, as determined by higher renal prostanoid levels and COX activity ratios of TXB 2/6-keto-PGF1␣, TXB2/PGE2, and 6-keto-PGF 1␣/PGE2. This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms. thromboxane; prostaglandin CYCLOOXYGENASE (COX

Selective cyclooxygenase-2 (COX-2) inhibitors appear to have beneficial renoprotective effects in most, but not all, renal disease conditions. The objective of our study was to examine the effects of COX-2 inhibition in a rat model of polycystic kidney disease. Four-week-old Han:SPRD-cy rats were given a standard rodent diet containing NS-398 (3 mg.kg body wt(-1).day(-1)) or a control diet without NS-398 for 7 wk. In diseased rats, selective COX-2 inhibition resulted in 18% and 67% reduction in cystic expansion and interstitial fibrosis, respectively, but no change in renal function. NS-398 also ameliorated disease-associated pathologies, such as renal inflammation, cell proliferation, and oxidant injury (by 33, 38, and 59%, respectively). Kidney disease was associated with elevated renal COX-1 and COX-2 enzyme activities, and NS-398 blunted the increase in COX-2 enzyme activity (as indicated by 21 and 28% lower renal thromboxane B2 and PGE2 levels, respectively). NS-398 reduced urinary excretion of prostanoid metabolites in diseased rats. In summary, COX-2 inhibition attenuated renal injury, reduced the elevated renal COX-2 activity, and ameliorated disease-related alterations in prostanoid production in this rat model of chronic renal disease.

Dietary soya protein substitution for casein initiated at weaning slows disease progression in animal models of chronic renal disease. As there is increasing evidence that fetal programming can have a significant impact on kidney physiology and function in offspring, the objective of the current study was to determine whether exposure to soya protein in the diet earlier than weaning would have further benefits. Han:SPRD-cy (cy/þ ) breeder rats were fed a casein-based or soya protein-based diet 2 weeks prior to mating, throughout pregnancy and during lactation. Following this maternal period, 3-week-old pups were given either the same or the alternate diet for a 7-week weaning period. Dietary soya protein compared with casein in the maternal or weaning period both independently resulted in less renal inflammation (macrophage infiltration lower by 24 % (P¼ 0·0003) and 32 % (P, 0·0001), respectively). When soya protein was given in both feeding periods, the effect was additive. Soya protein substitution for casein resulted in less oxidative damage as indicated by 28 % lower oxidized-LDL staining (P¼ 0·013) when present in the maternal period, or in the weaning period (by 56 %, P,0·0001). Renal cell proliferation was reduced by 29-33 % (P,0·05) in rats given soya protein whether the exposure was during the maternal or weaning period. Soya protein compared with casein in the maternal period also resulted in 33 % (P¼ 0·0013) less proteinuria, indicating superior renal function. Dietary soya protein during pregnancy and lactation represents a potential preventative approach in treating for those with congenital kidney diseases.

Dietary flax oil (FO) retards disease progression in growing or adult animal models of kidney disease. To determine whether dietary flax oil during the perinatal period would alter renal disease progression in offspring, Han-SPRD-cy rats with inherited cystic kidney disease were given diets with either 7% FO or corn oil (CO), throughout pregnancy and lactation. At 3 wk of age, offspring were then given either the same or the alternate diet for 7 wk. Rats given FO during the maternal period had 15% less renal cyst growth compared with rats given FO only in the postweaning period. Dietary FO, compared with CO, in the maternal period also resulted in 12% lower cell proliferation and 15% less oxidant injury in diseased kidneys of offspring. Including FO in both the maternal and postweaning period resulted in 29 -34% less renal interstitial fibrosis and 22-23% lower glomerular hypertrophy. Along with improved histology, these rats exhibited 13% less proteinuria and 30% lower creatinine clearance when dietary FO was given in the maternal period. The potential for dietary FO during pregnancy and lactation to positively modulate adult renal disease has significant implications for the 1 in 1000 individuals with congenital cystic kidney disease.

Background/Aims: Dietary soy protein and flax oil retard kidney disease progression when initiated in the early stages of disease in several experimental models, including the Han:SPRD-cy rat. However, individuals with kidney disease often do not become aware of their condition until injury to the kidney is extensive. The objective of this study was to determine whether initiating these interventions in established disease would alter further progression of renal injury. Methods: Two-month-old adult male Han:SPRD-cy rats were given either a flax oil diet (7% flax oil), a soy protein diet (20% soy protein) or a control diet (7% corn oil, 20% casein) for 4 months. Renal disease progression was assessed by examining morphological, immunohistochemical and biochemical parameters. Results: Compared to controls, there was 21–24% less staining of proliferating cells, 21–24% less oxidative damage and 13–15% less renal inflammation in kidneys from rats given dietary soy protein and flax oil. Renal cystic growth and fibrosis and serum creatinine levels were not altered by these dietary treatments. Conclusions: Late intervention with dietary soy protein and flax oil reduces some disease-associated pathologies in established renal disease in Han:SPRD-cy rats. The potential benefits of the antioxidant and anti-inflammatory effects on ultimate renal disease outcome in the long term remains to be determined.

Increasing evidence in human chronic kidney disease and in animal models indicates the potential utility of dietary soy protein in the treatment of this disorder. A model in which a beneficial soy protein effect has been consistently demonstrated is the Han:SPRD-cy rat model of polycystic kidney disease. Therefore, since dietary soy protein alters renal hemodynamics and prostanoid production, the effects of dietary soy protein on renal prostanoids and related rate-limiting enzymes were examined. Normal and diseased weanling rats were given diets containing casein or soy protein for 7 wk. At 10 wk of age, renal levels of thromboxane B(2) (TXB(2), stable metabolite of TXA(2)), prostaglandin E(2) (PGE(2)) and 6-keto PGF(1alpha) (stable metabolite of PGI(2)) and activities of cyclooxygenase 1 (COX1) and COX2 were elevated in diseased compared to normal kidneys. Soy protein feeding resulted in 49% lower in vitro steady-state levels of TXB(2), and 76% less 6-keto PGF(1alpha) produced by COX1 activity in diseased kidneys, while not altering these parameters in normal kidneys. It also resulted in 47% less TXB(2) and 36% lower 6-keto PGF(1alpha) produced by COX2 activity in diseased kidneys. The relative effect of soy protein feeding on COX2 activity was in the order of TXB(2) > 6-keto PGF(1alpha) > PGE(2). Diseased kidneys had elevated protein and mRNA levels of cytosolic phospholipase A(2) (cPLA(2)) and COX1 and lower levels of COX2. Dietary soy protein attenuated the protein levels of cPLA(2) in diseased kidneys, and reduced COX2 mRNA expression in both normal and diseased kidneys. Dietary soy protein therefore reduced the levels of specific renal prostanoids, cPLA(2) and COX enzymes in this model of polycystic kidney disease, a model in which soy protein has been demonstrated to reduce disease progression.

No abstract