High linoleic acid diets ameliorate diabetic nephropathy in rats.

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

A diet containing n-3 and n-6 fatty acids favorably alters the renal phospholipids, eicosanoid synthesis and plasma lipids in nephrotic rats.

The nephrotic syndrome was induced in rats by intravenous adriamycin (3 mg/kg). The rats were then divided into four groups which, for six weeks, were pair-fed diets containing beef tallow (BT), fish oil (FO), a source of n-3 fatty acids, evening primrose oil (EPO), a source of n-6 fatty acids, or a combination of evening primrose oil and fish oil, 75:25 (EPO:FO). The fat content of the diets was 15%. Significant incorporation of the fatty acids into kidney phospholipids was demonstrated. Diets containing FO, EPO and EPO:FO lowered plasma triglycerides and total cholesterol levels as compared with diets containing BT. Only EPO:FO raised high density lipoprotein (HDL) cholesterol levels, as compared with BT. The combination EPO:FO prevented the tenfold suppression of aortic 6-keto-PGF1 alpha caused by FO. These changes in plasma lipids and eicosanoid production are potentially antiatherogenic and may prevent glomerular sclerosis. The combination of EPO and FO, containing n-6 and n-3 fatty acids may offer advantages over either family of fatty acids in this model of nephrotic syndrome.

The influence of n-6 and n-3 fatty acids on kidney phospholipid composition and on eicosanoid production in aging rats.

Changes in eicosanoid production may contribute to some of the complications of the aging process such as atherosclerosis and glomerular sclerosis. Polyunsaturated fatty acids of the n-6 and n-3 series are precursors of eicosanoids. We fed diets containing safflower oil as a source of n-6 fatty acids, fish oil as a source of n-3 fatty acids or beef tallow as a source of saturated fats to three groups of normal rats from 2-18 months of age. We demonstrated incorporation of the n-3 fatty acids, 20:5n-3 and 22:6n-3 into kidney phospholipids. Feeding of the diet containing n-3 fatty acids was associated with a markedly decreased glomerular production of PGE, 6-keto-PGF1 alpha and TXB2. It also decreased the aortic production of 6-keto-PGF1 alpha and platelet production of TXB2. No significant effect of n-6 fatty acids on dienoic eicosanoid production was observed. There were no adverse effects on kidney function as measured by urinary protein excretion and serum creatinine levels or on renal morphology by any diet. A diet enriched in n-3 fatty acids for 18 months remains effective in decreasing dienoic eicosanoids in the aging rat.

Renal prostaglandin production is increased during abdominal sepsis in the rat and unaffected by the infusion of different amino acid formulations.

Renal prostaglandin (PG) production was studied in 32 laparotomized (control) and 33 septic rats (cecal ligation and puncture). Control and septic rats were infused for 18 hr with 5% glucose or 5% glucose and one of three amino acid formulations containing 22, 35, or 45% branched chain amino acids. When comparing renal PG production from endogenous precursors in septic versus control rats, significant increases (P less than 0.01) could be detected for PGE2, 6-keto-PGF1 alpha, and TxB2. The infusion of either 5% glucose alone or 5% glucose with 4.25% of any of the three amino acid formulations tested did not change renal PG production in either control or septic rats.

The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat.

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.

Beneficial effects of polyunsaturated fatty acids in partially nephrectomized rats.

Evening primrose oil, safflower oil, and salmon oil, all with high polyunsaturated fatty acid content, were fed to partially nephrectomized rats; the effects were compared to those of feeding beef tallow. All three oils had favorable effects on progression of renal failure, salmon oil on kidney histology as well. The changes induced in platelet production of thromboxane A2, and in the renal production of various eicosanoids may explain the protective role of these oils.

Measurement of prostaglandin E3 and other eicosanoids in biologic samples using high pressure liquid chromatography and radioimmunoassay.

A method to measure PGE3 in biologic samples is described. Complete resolution of PGE3 from PGE1 and PGE2 is achieved by reversephase high pressure liquid chromatography. Quantification is carried out by radioimmunoassay using an antibody directed against PGE2 that has high cross-reactivity with PGE3. Using this method, a marked increase in PGE3 production by mouse kidney tissue and in rat urine was demonstrated after supplemental feeding of omega-3 fatty acids. This method can also be applied to measurement of 6-keto-PGF1 alpha and TXB2 in the same samples.

Muscle prostaglandin production in the rat. Effect of abdominal sepsis and different amino acid formulations.

Recent in vitro studies attribute regulatory functions to prostaglandins (PGs) in muscle protein metabolism, particularly enhancing proteolysis. In the present study, the amount of muscle PG production from endogenous precursors was determined in control and septic animals (cecal ligation and puncture) that were infused with 5% dextrose or dextrose with three amino acid formulations differing in their branched-chain amino acid (BCAA) content. We could not detect any differences in prostaglandin E, 6-keto-prostaglandin F1 alpha, and thromboxane B2 production between control and septic animals. Furthermore, the infusion of BCAAs, which have previously been shown to be nitrogen sparing following injury, did not influence the production of any of the PGs studied in either control or septic muscle. It is likely that the effects of the BCAAs on muscle synthesis and degradation are independent of the PGs.

Effects of a dietary prostaglandin precursor on the progression of experimentally induced chronic renal failure.

The effect of increasing a dietary PG precursor on the progression of chronic renal failure was studied in the partially nephrectomized rat. NLA or HLA diets were pair-fed to groups of 3/4-nephrectomized and sham-operated rats. Serum creatinine and urinary protein excretion were measured serially. Nephrectomized rats on the NLA diet had progressive deterioration of renal function, the serum creatinine level rising to 1.55 mg/dl by week 20. At week 20, by contrast, nephrectomized rats on the HLA diet maintained stable renal function; the serum creatinine level was 0.97 mg/dl at week 20. Urinary protein excretion was significantly lower and glomerular sclerosis was prevented in the rats fed the HLA diet. No changes were observed in the levels of blood pressure, serum cholesterol, or serum triglycerides as an effect of the diet. Increased PGE2 production, measured by radioimmunoassay in the renal cortex of rats on the HLA diet, suggested that the protective effect upon renal function in this model of chronic renal failure may be mediated by increased renal cortical PG formation.