No abstract

SUMMARY:Angiotensin II (AngII) plays an important role in renal damage by acting on hemodynamics, cell-growth, proliferation, and fibrosis, mainly by effects on the AngII type 1 (AT 1 ) receptor. The AT 1 receptor activates several intracellular signaling molecules such as mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, but their role in AngII-mediated renal damage is not well characterized. We therefore investigated whether pharmacologic blockade of ERK and p38 could prevent renal damage in high-renin homozygous transgenic rats (Ren2), with the effects of an AT 1 receptor antagonist (AT 1 -RA) as a reference. Seven-week-old homozygous Ren2 rats were treated with low-dose AT 1 -RA candesartan, ERK inhibitor tyrphostin, or p38 inhibitor SB239063 for 4 weeks. Untreated Ren2 and SD rats served as controls. Blood pressure was measured at 7 and 11 weeks. At 11 weeks, plasma renin activity (PRA) and serum aldosterone were determined, and the animals were killed. Kidney sections were scored for glomerular and interstitial smooth muscle actin and glomerular desmin expression as early markers for renal damage. Mesangial matrix expansion was determined as a marker for structural damage. PRA and aldosterone levels were elevated in untreated Ren2 rats in comparison to SD controls. AT 1 -RA further increased PRA but decreased aldosterone. All parameters of renal damage were elevated in untreated Ren2 rats. Blood pressure was not elevated at week 7 in Ren2 and not affected by either treatment. Mild signs of hypertensive damage were found in untreated Ren2 rats. All interventions significantly diminished damage to glomerular epithelium and interstitium. In addition, AT 1 receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT 1 -RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage. (Lab Invest 2003, 83:1761-1770.

Objective: Prophylactic insulin treatment has been demonstrated to reduce diabetes development in the diabetes-prone bio-breeding (DP-BB) rat. These prophylactic insulin treatments were given from 50 to 150 days of age. However, several data indicate that the diabetogenic process in DP-BB rats starts well before day 50. Design and methods: DP-BB rats were given bovine insulin pellets from 21 to 60 days of age, from 21 to 100 days of age and from 60 to 100 days of age. At 160 days of age a glucose tolerance test was performed to establish b-cell function and pancreata collected for histological analysis. Results: Prophylactic insulin treatment from 21 to 100 days of age gave a 42% reduction of diabetes incidence. The other treatment protocols had no effect. Non-diabetic rats treated with insulin from day 21 to 100 showed normal glucose tolerance and no sign of insulitis at 160 days of age. Non-diabetic rats of the control group and the other treatment groups showed normal glucose tolerance, but a slight increase of insulitis. Interestingly, the 21-100 day treated rats showed reduced serum levels of anti-colloid antibodies as compared with the control group. Conclusions: These results show that short-term prophylactic insulin treatment cannot prevent diabetes and thyroiditis development in DP-BB rats. The prophylactic treatment must start well before 60 days of age and be prolonged into the phase when the rats normally become diabetic to reduce diabetes incidence. These findings imply that in the human situation prophylactic insulin treatment must be prolonged over the normal range of diabetes onset.

Besides genetic background, environmental factors such as food ingredients and viral infections have been indicated as important and possibly decisive elements for the induction of insulin-dependent diabetes mellitus (IDDM). Our data show that diabetes development in diabetes-prone (DP)-BB rats can be delayed and prevented by prolonging the nursing period of these rats. These results provide experimental evidence strengthening human epidemiological data that the duration of exclusive breastfeeding influences diabetes development later in life.Most human epidemiological data suggest that a short, as opposed to a long, duration of exclusive breastfeeding is related with an increased risk for IDDM development [1,2,3,4,5]. The introduction of cow's milk and wheat proteins at a young age has been suggested as potential diabetogenic risk factors for infants at risk of developing diabetes [1,2,3,4,5]. The importance of food ingredients in IDDM is further illustrated by the fact that the development of diabetes is reduced in DP-BB rats receiving a special diet in which hydrolysed casein is the sole source of protein [6]. Since, in epidemiological studies the period of nursing is established using questionnaires, the exact duration of breastfeeding remains unclear and duration of breastfeeding varies considerably between the siblings [1,2,3,4,5]. DP-BB rats normally spontaneously develop diabetes between 60 and 160 days of age and are used as an animal model for the study of Type 1 diabetes. In the DP-BB rat model for the study of diabetes, the period of suckling can be established precisely. To investigate whether a relation exists between the duration of exclusive breastfeeding and the onset of diabetes