Association of renal injury with nitric oxide deficiency in aged SHR: prevention by hypertension control with AT1 blockade

BACKGROUND: Aged spontaneously hypertensive rats (SHR) develop end-stage renal disease resembling that of uncontrolled essential hypertension in humans. Nitric oxide (NO) and angiotensin II (Ang II) play an important role in the regulation of blood pressure and the growth of vascular smooth muscle and renal mesangial cells. The relationship between renal NO system, Ang II activity and renal injury in aged SHR is not fully understood. METHODS: The 8-week-old SHR were randomized into losartan-treated (30 mg/kg/day for 55 weeks) and vehicle treated groups. The age-matched Wistar-Kyoto rats (WKY) served as controls. Renal histology and tissue expressions of endothelial and inducible NO synthases (eNOS and iNOS) and nitrotyrosine were examined at 63-weeks of age. RESULTS: Compared to the WKY group, untreated SHR showed severe hypertension, proteinuria, renal insufficiency, a twofold decrease in renal tissue eNOS and iNOS expressions and massive nitrotyrosine accumulation. This was associated with severe glomerulosclerosis, tubular atrophy and interstitial fibrosis. Losartan therapy normalized blood pressure, prevented proteinuria and renal insufficiency, abrogated the fall in renal eNOS and iNOS protein contents, mitigated renal nitrotyrosine accumulation, and prevented the histological abnormalities found in the untreated SHR. CONCLUSIONS: Aged SHR exhibit severe renal lesions with acquired NO deficiency that are prevented by hypertension control with AT1 blockade. These findings point to the possible role of NO deficiency in the pathogenesis of renal lesions in aged SHR.     

Reversibility of chronic experimental syndrome X by diet modification

This study was designed to examine whether abnormalities that comprise the metabolic syndrome, including insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, and obesity, are reversible by diet. Female Fischer rats were placed on either a high-fat, refined-carbohydrate (HFS) diet or low-fat, complex-carbohydrate (LFCC) diet for a period of 20 months. After 20 months, a group of HFS rats were switched to the LFCC diet (HFS/LFCC) for a period of 2 months. Skeletal muscle glucose transport, plasma insulin, systolic blood pressure, and plasma lipids were measured in all groups after 22 months. Energy intake and body weight were measured weekly. In the HFS group, insulin-stimulated glucose transport was significantly reduced (67+/-4 versus 98+/-4 pmol. mg(-)(1). 15 s(-)(1)), whereas plasma insulin (300+/-49 versus 82+/-8 pmol/L), blood pressure (147+/-4 versus 123+/-4 mm Hg), plasma triglycerides (2.58+/-0.31 versus 0.39+/-0.04 mmol/L), LDL cholesterol (C) (3.45+/-0.40 versus 0.89+/-0.06 mmol/L), LDL-C to HDL-C ratio (2.9+/-0.1 versus 2.2+/-0.1), VLDL-C (1.53+/-0.23 versus 0.37+/-0.07 mmol/l), Total-C (5.56+/-0.58 versus 1.49+/-0.10 mmol/L), and body weight (360+/-11 versus 260+/-5 g) were all significantly elevated compared with the LFCC. Energy intake did not differ significantly; however, the LFCC had a much poorer feed efficiency. Conversion to a LFCC diet for 2 months led to normalization of glucose transport, blood pressure, plasma insulin, and VLDL-C and significant amelioration of obesity and other lipid abnormalities. These results demonstrate that syndrome X induced by an inappropriate diet is reversed with implementation of a low-fat, unrefined-carbohydrate diet without caloric restriction and suggest that diet may be a possible treatment for multiple simultaneous cardiovascular risk factors.     

Intrapulmonary shunting in the biliary atresia/polysplenia syndrome: reversal after liver transplantation

One hundred and seventy three children, including 93 with biliary atresia, received liver grafts at Addenbrooke's Hospital between 1983 and 1993. Of these, only seven developed cyanosis due to intrapulmonary shunting as a complication of their liver disease, and all seven of these had the biliary atresia/polysplenia syndrome. Intrapulmonary shunting was confirmed by a radioisotope scan in four children. Only one child with the syndrome did not have cyanosis when undergoing transplantation. Seven of the eight children are alive 6-54 months after transplantation, with normal pulmonary and hepatic function. Cyanosis recurred in one child who developed chronic rejection with liver failure. In conclusion: (a) there is a strong association between the biliary atresia/polysplenia syndrome and cyanosis due to intrapulmonary shunting; (b) intrapulmonary shunting is fully reversible after successful liver transplantation; and (c) cyanosis, once present, is progressive, and these children should be considered for liver transplantation as soon as it occurs.     

Neurological crisis in hereditary tyrosinaemia and complete reversal after liver transplantation

A 19 month old Indian girl with tyrosinaemia developed a severe generalised neuropathy involving both phrenic nerves. Treatment with haemarginate failed to improve her condition. After liver transplantation the raised concentrations of the neurotoxin delta amino-laevulinic acid returned to normal and gradual but complete neurological recovery occurred over a period of 13 months.     

Gastrointestinal Pathology in Patients with Chronic Renal Failure Associated with Spinal Cord Injury

Clinical and histological data on 23 consecutive patients with end stage renal disease associated with spinal cord injury were reviewed. They had been maintained on hemodialysis for a mean duration of 17 months. Various gastrointestinal abnormalities were detected in 20 patients. Thirteen patients (56%) were found to have secondary amyloidosis involving the gastrointestinal tract. The incidence of peptic ulcer disease and cholelithiasis were both higher than that reported in postmortem examinations of the general population.     

HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X

BACKGROUND: Long-term consumption of Western diets can lead to acquired syndrome X, which presents with obesity, insulin resistance, hypertension, hyperlipidemia, and risk of atherosclerotic cardiovascular disease. While plasma lipid abnormalities in syndrome X have been well characterized, their molecular basis remains unclear. This study explored potential mechanisms of hypercholesterolemia in diet-induced syndrome X. METHODS: Female Fischer rats were fed a high-fat, refined-carbohydrate (sucrose) diet (HFS) or standard rat chow (low-fat, complex carbohydrate, LFCC) for 20 months. Plasma lipids and hepatic tissue mRNA, protein, and/or activities of the key enzymes and receptors involved in cholesterol metabolism were determined. RESULTS: The HFS group exhibited hypertension, hyperlipidemia, insulin resistance, obesity, significant down-regulation of hepatic cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol catabolism) and low-density lipoprotein (LDL) receptor (LDL-R, the primary pathway of LDL clearance). In contrast, hepatic tissue acyl-coenzyme A:cholesterol acyltransferase (ACAT-2, the primary enzyme involved in intracellular esterification of cholesterol) and scavenger-receptor class B, type 1 (SR-B1 or HDL receptor) were up-regulated. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA expression was increased, its protein abundance and activity were unchanged, and HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio was increased in HFS-fed animals. CONCLUSION: Hypercholesterolemia in diet-induced syndrome X is associated with depressed cholesterol 7alpha-hydroxylase, diminished LDL-R, elevated ACAT, and increased HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio. These findings point to impaired hepatic catabolism and uptake of cholesterol and inappropriate cholesterol production capacity as the underlying causes of hypercholesterolemia in rats with diet-induced syndrome X.     

Evolution of renal interstitial inflammation and NF-kappaB activation in spontaneously hypertensive rats

Lymphocytes and macrophages infiltrate the kidney of spontaneously hypertensive rats (SHR) and interventions leading to their reduction are associated with improvement of the hypertension. The present studies examined the evolution of the interstitial inflammation in the natural course of the SHR to gain insight on the potential role of interstitial immune cell accumulation in the development of hypertension. We studied SHR and control WKY rats at 3 weeks (SHR-3 wk group, n = 11 and WKY-3 wk group, n = 10), 11 weeks (SHR-11 wk group, n = 5 and WKY-11 wk group, n = 5) and 24 weeks (SHR-24 wk group, n = 10 and WKY-24 wk group, n = 10). The SHR-3 wk group was normotensive and older SHR developed hypertension that was severe in the SHR-24 wk group. Tubulointerstitial accumulation of lymphocytes, macrophages, angiotensin II-positive cells, cells expressing the p65 DNA-binding subunit of NF-kappaB and activation of NF-kappaB in the kidney were all significantly increased (p < 0.01) in the prehypertensive SHR-3 wk group and augmented progressively, with the highest values in the SHR-24 wk group. The SHR-24 wk group showed increased (p < 0.001) helper (CD4) T cell infiltration and a high CD4/CD8 ratio. These findings are consistent with the possibility that activation of NF-kappaB and renal interstitial infiltration of immune cells may be part of the pathophysiologic process that drives hypertension in the SHR.