Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats.

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.

Short-term dietary adjustment with a hydrolyzed casein-based diet postpones diabetes development in the diabetes-prone BB rat.

From earlier studies it appears that weaning associated changes in the animal's physiology and that of the pancreas in particular, render diabetes-prone Bio-Breeding (DP-BB) rats susceptible to the induction and development of insulin-dependent diabetes mellitus (IDDM). In this study we tested whether a short-term dietary adjustment at weaning would influence the development of diabetes later in life. For this purpose a diet in which the protein source was replaced with hydrolyzed casein (HC) was given to the rats from weaning to 60 days of age and from weaning to 130 days of age. The control group received the cereal-based standard diet throughout the experiment. The short-term dietary adjustment resulted in a significant delay of diabetes development. The rats fed the HC diet from weaning to 130 days of age showed a lower incidence of diabetes at 130 days of age. No differences were seen in the histological insulitis scores between the rats of the different treatment groups. Interestingly, when testing (mucosal) immune functions of short-term HC-fed rats, their mesenteric lymph node cells (MLNC) showed increased interferon-gamma (IFN-gamma) and reduced interleukin-10 (IL-10) production after in vitro stimulation. These results demonstrate that short-term dietary adjustments at a young age can influence the course of diabetes later in life. The shift in cytokine profile of MLNC of the HC-fed rats suggests that mechanisms involved can be at the level of both the (mucosal) immune system and the beta cell.