Abstract-Embryo cross-transplantation and cross-fostering between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) suggest that perinatal environment modulates the genetically determined phenotype. In SHR the balance between NO and reactive oxygen species (ROS) is disturbed. We hypothesized that increasing NO and diminishing ROS in perinatal life would ameliorate hypertension in adult SHR. Pregnant SHR and WKY and their offspring received L-arginine plus antioxidants (vitamin C, vitamin E, and taurine) during the last 2 weeks of pregnancy and then until either 4 or 8 weeks after birth. Systolic blood pressure (SBP) and urinary excretion of protein, nitrates (NO x ), and thiobarbituric acid reactive substances (TBARS) were measured. At 48 weeks of age rats were euthanized for glomerular counts. Perinatal supplements reduced SBP persistently in SHR and prevented the SBP increase observed in aging WKY. Initially NO x excretion was lower and TBARS excretion higher in SHR than WKY. There was a direct effect on NO x excretion in supplemented pregnant SHR and their offspring, but no increase was observed after stopping the supplements. TBARS excretion was only depressed up to 14 weeks by the supplements despite persistent differences in SBP. Consistent effects on nephron number were absent. Mild proteinuria, present in control SHR at 48 weeks, was prevented in all supplemented rats. In animal models there is ample evidence to support this, although a common denominator has not been found. Both embryo cross-transferring and cross-fostering studies between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) resulted in reduced BP in SHR offspring, 3,4 suggesting that either nongenetic causal factors leading to hypertension or consequences of hypertension itself are transmitted to the neonates. Most studies have focused on maneuvers such as restriction of maternal nutrition 5,6 to simulate the Barker proposition that disadvantageous perinatal environmental factors increase BP in the offspring. 1 No studies have addressed whether the reverse holds true (ie, whether advantageous perinatal factors may exist).In this study we focused on the imbalance between NO and reactive oxygen species (ROS) activity, which forms part of a common pathway for endothelial dysfunction and, possibly, hypertension. 7 The SHR is a model for this imbalance; in SHR production of superoxide (O 2 Ϫ ) and other ROS is upregulated in the cardiovascular system and kidney. 8,9 Reports on NO production are conflicting, 10,11 but it is accepted that overall NO availability is decreased in SHR, possibly as a result of its inactivation by O 2 Ϫ . Whether this imbalance also influences development in SHR during pregnancy and lactation is unknown. Hence we first studied whether the imbalance between NO and ROS is already present in young SHR and whether transient perinatal exposure of SHR to dietary supplements that supposedly reduce O 2 Ϫ and support NO formation induce a sustained alteration of this balance after stopping the ...

Summary Unilateral ureteric obstruction (UUO) is one of the most commonly applied rodent models to study the pathophysiology of renal fibrosis. This model reflects important aspects of inflammation and fibrosis that are prominent in human kidney diseases. In this review, we present an overview of the factors contributing to the pathophysiology of UUO, highlighting the role of oxidative stress.

There are major strain differences in the proteinuria and renal inflammatory response of mice to albumin overload, which are not due to structural variation in the filtration barrier but possibly to functional differences in glomerular protein permeability.

Bone morphogenetic protein-6 (BMP-6) suppresses inflammatory genes in renal proximal tubular cells and regulates iron metabolism by inducing hepcidin. In diabetic patients, an increase of myofibroblast progenitor cells (MFPCs), also known as fibrocytes, was found to be associated with decreased BMP-6 expression. We hypothesized that loss of endogenous BMP-6 would aggravate renal injury and fibrosis. Wild type (WT) and BMP-6 null mice underwent unilateral ureteral obstruction. In WT mice, ureteral obstruction down-regulated BMP-6. Obstructed kidneys of BMP-6 null mice showed more casts (1.5-fold), epithelial necrosis (1.4-fold), and brush border loss (1.3-fold). This was associated with more inflammation (1.8-fold more CD45(+) cells) and more pronounced overexpression of profibrotic genes for αSMA (2.0-fold), collagen I (6.8-fold), fibronectin (4.3-fold), CTGF (1.8-fold), and PAI-1 (3.8-fold), despite similar BMP-7 expression. Also, 1.3-fold more MFPCs were obtained from BMP-6 null than from WT mononuclear cell cultures, but in vivo only very few MFPCs were observed in obstructed kidneys, irrespective of BMP-6 genotype. The obstructed kidneys of BMP-6 null mice showed 2.2-fold more iron deposition, in association with 3.3-fold higher expression of the oxidative stress marker HO-1. Thus, ureteral obstruction leads to down-regulation of BMP-6 expression, and BMP-6 deficiency aggravates tubulointerstitial damage and fibrosis independent of BMP-7. This process appears to involve loss of both direct anti-inflammatory and antifibrotic action and indirect suppressive effects on renal iron deposition, oxidative stress, and MFPCs.