Summary. The mechanism by which expansion of extracellular fluid volume with isotonic saline suppresses reabsorption in the proximal tubule was studied in rats by examining the relations among glomerular filtration rate (GFR), absolute and fractional reabsorption of filtrate, intrinsic reabsorptive capacity (rate of reabsorption per unit tubular volume), transit time, and tubular volume.Saline infusions reduced the per cent of the glomerular filtrate reabsorbed in the proximal tubule from 50% during antidiuresis to 25% during saline diuresis. The suppression of proximal reabsorption was the result of two factors: 1) a 30% reduction of intrinsic reabsorptive capacity, and 2) a 26% reduction of tubular volume per unit GFR.GFR invariably rose during saline diuresis. However, prevention of the rise in GFR by aortic clamping had no effect on either the inhibition of intrinsic reabsorptive capacity or the reduction in tubular volume per unit GFR produced by saline infusions. Expansion of extracellular fluid volume with isotonic saline, therefore, depressed intrinsic reabsorptive capacity and tubular volume per unit GFR by some mechanism completely independent of GFR.The effects of furosemide administration were contrasted with those of saline infusions. Furosemide inhibited intrinsic reabsorptive capacity by 40% but had no significant effect on proximal fractional reabsorption. The failure to suppress fractional reabsorption was the consequence of a disproportionate rise in tubular volume (relative to GFR) that was sufficient to completely overcome the inhibition of intrinsic reabsorptive capacity. Inhibition of intrinsic reabsorptive capacity alone, therefore, will not result in a net suppression of reabsorption of filtrate in the proximal tubule. We concluded that, although intrinsic reabsorptive capacity was inhibited during saline diuresis, the critical factor responsible for translating this inhibition into effective net suppression of proximal reabsorption was the observed reduction in tubular volume per unit GFR. IntroductionThe diuresis induced by expanding extracellular fluid (ECF) volume with isotonic saline is due in part to a decrease in the fraction of the glomerular filtrate reabsorbed in the proximal convoluted tubule (1, 2). However, the mechanism by which saline infusions depress fractional reabsorption in the proximal tubule has not been examined.Previous studies in our laboratory (3, 4) explored the factors controlling fractional reabsorption in the proximal tubule under conditions in which glomerular filtration rate (GFR) was varied but ECF volume was kept constant. We found that the absolute rate of reabsorption during both aortic constriction and increased ureteral pressure was a direct function of tubular volume. When GFR was acutely reduced by constricting the aorta, tubular volume decreased proportionately to GFR; this resulted in a proportionate decrease in the reabsorptive rate, thereby maintaining constant fractional reabsorption. In contrast, when GFR was decreased by acutely elevating ur...

Unilateral ureteral obstruction (UUO) leads to fibrosis of the obstructed kidney. We tested the hypothesis that interstitial fibrosis in UUO results, at least in part, from enhanced expression of transforming growth factor-beta (TGF-beta) which in turn is regulated by local angiotensin II (Ang II) generation. (The generic name TGF-beta is used to discuss properties shared by all isoforms, but special reference to other isoforms is made when specifically needed.) Using Northern blot and immunohistochemical analysis, we examined the expression of TGF-beta in rat kidneys after 24 hours (aUUO) and one week (cUUO) of obstruction. Obstructed kidneys from both periods had increased interstitial and perivascular TGF-beta immunoreactivity compared to contralateral and sham kidneys, in which immunostaining was confined to the inner medulla. Relative abundance of all TGF-beta mRNA isoforms were higher in the obstructed than in contralateral and sham kidneys in both aUUO and cUUO. Expression of TGF-beta isoforms varied according to site (cortex vs. medulla), segment of the nephron, type of cells and duration of the obstruction. The increase in TGF-beta immunoreactivity and mRNA levels in aUUO and cUUO was almost totally abolished by pretreatment with losartan. We conclude that in UUO: (a) TGF-beta gene expression is increased and differentially regulated; (b) Ang II, at least partially, mediates the overexpression of TGF-beta gene; and (c) Ang II may play a central role in fibrogenesis in this and other models of tubulointerstitial disease.

Excess body weight, high blood pressure, and insulin resistance together have been denominated the metabolic syndrome. In this review, we analyze the potential role of angiotensin II (Ang II) and reactive oxygen species in mediating inflammation in the metabolic syndrome. Ang II induces pro-inflammatory genes and other pro-inflammatory substances and increases oxidative stress that could damage endothelium, myocardium, and renal tissue. Activation of nuclear factor-kappaB and NAD(P)H oxidase are fundamental steps in these pro-inflammatory mechanisms in which intramitochondrial oxidative stress could play a critical role. This sequence of events might explain why reduction in Ang II synthesis by angiotensin-converting enzyme inhibitors (ACEIs) and Ang II type 1 (AT1) receptor blockers (ARBs) have a protective effect against cardiovascular disease.

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Unilateral ureteral obstruction (UUO) alters the expression of genes encoding for the renin-angiotensin system (RAS). We tested the hypothesis that changes in RAS genes expression occur soon after obstruction. Indeed, measurements during the first 24 hours of UUO showed up-regulation of renin mRNA in the obstructed kidney at 1 hour. UUO also led to increases in PRA and renal renin content, ACE activity and Ang II concentration in the experimental kidney. The obstructed kidney relative abundance of renin mRNA was increased compared to basal at 1, 2, 6, and 24 hours; the contralateral kidney renin mRNA expression was reduced. AT1-R mRNA expression was diminished at 6 and 24 hours in the obstructed kidney compared to contralateral and sham kidneys. ACE activity was up-regulated in the obstructed kidney and transiently down-regulated in the contralateral kidney. These findings show for the first time that activation of the RAS results from as little as 1 hour of UUO and that up-regulation of renin mRNA and ACE activity lead to increase Ang II production which down-regulates AT1-R mRNA as early as 6 hours post-UUO. These studies establish a pattern of sequential, differential regulation of the RAS genes in acute UUO that provide an explanation for the hemodynamic changes in this condition.