Uninephrectomized Animals Research Articles

Effect of cocoa powder on hypertension and antioxidant status in uninephrectomized hypertensive rats.

Background and Aim:High salt diet and uninephrectomy are associated with high blood pressure with attendant cardiovascular disease conditions such as hypertension, renal damage, myocardial infarction, and stroke. The aim of this study was to investigate the beneficial effects of consumption of cocoa and cocoa-containing products in the management of high blood pressure in uninephrectomized hypertensive rats.Materials and Methods:The effect of cocoa powder on blood pressure, markers of inflammation, oxidative stress, and histopathology were investigated in uninephrectomized animals fed with cocoa feed alone or in combination with a high salt diet. Male rats were randomly divided into five groups: Group A was the control group and fed with normal feed alone, Group B was fed with cocoa feed alone, Group C was fed with high salt diet (8% salt), GroupD was fed with cocoa-feed compounded with 8% salt for 4weeks after uninephrectomy, and GroupE was uninephrectomized rats on a normal diet. The left kidneys of animals in GroupsC, D, and E were removed by surgery. After 4weeks of treatment, the systolic, diastolic, and mean arterial blood pressure was measured. The serum markers of renal damage and oxidative stress were determined. Histological examination was also performed on renal and cardiac tissues.Results:Results showed significant increases in biomarkers of oxidative stress, inflammation, and renal damage with a concomitant decrease in antioxidant status in hypertensive uninephrectomized rats. Cocoa feed, however, significantly improved blood pressure and nitric oxide bioavailability, antioxidant status and reduced markers of inflammation and oxidative stress.Conclusion:These findings show that cocoa powder could be used to maintain blood pressure levels in hypertensive rats through its antioxidant capacity.

Cyclooxygenase-2, prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney.

Hyperfiltration subjects podocytes to increased tensile stress and fluid flow shear stress (FFSS). We showed a 1.5- to 2.0-fold increase in FFSS in uninephrectomized animals and altered podocyte actin cytoskeleton and increased synthesis of prostaglandin E2 (PGE2) following in vitro application of FFSS. We hypothesized that increased FFSS mediates cellular changes through specific receptors of PGE2. Presently, we studied the effect of FFSS on cultured podocytes and decapsulated isolated glomeruli in vitro, and on solitary kidney in uninephrectomized sv129 mice. In cultured podocytes, FFSS resulted in increased gene and protein expression of cyclooxygenase (COX)-2 but not COX-1, prostanoid receptor EP2 but not EP4, and increased synthesis and secretion of PGE2, which were effectively blocked by indomethacin. Next, we developed a special flow chamber for applying FFSS to isolated glomeruli to determine its effect on an intact glomerular filtration barrier by measuring change in albumin permeability (Palb) in vitro. FFSS caused an increase in Palb that was blocked by indomethacin (P < 0.001). Finally, we show that unilateral nephrectomy in sv129 mice resulted in glomerular hypertrophy (P = 0.006), increased glomerular expression of COX-2 (P < 0.001) and EP2 (P = 0.039), and increased urinary albumin excretion (P = 0.001). Activation of the COX-2-PGE2-EP2 axis appears to be a specific response to FFSS in podocytes and provides a mechanistic basis for alteration in podocyte structure and the glomerular filtration barrier, leading to albuminuria in hyperfiltration-mediated kidney injury. The COX-2-PGE2-EP2 axis is a potential target for developing specific interventions to ameliorate the effects of hyperfiltration-mediated kidney injury in the progression of chronic kidney disease.

Reduced nephron endowment due to fetal uninephrectomy impairs renal sodium handling in male sheep

Reduced nephron endowment is associated with development of renal and cardiovascular disease. We hypothesized this may be attributable to impaired sodium homoeostasis by the remaining nephrons. The present study investigated whether a nephron deficit, induced by fetal uninephrectomy at 100 days gestation (term=150 days), resulted in (i) altered renal sodium handling both under basal conditions and in response to an acute 0.9% saline load (50 ml.kg-1 of body weight.30 min-1); (ii) hypertension and (iii) altered expression of renal channels/transporters in male sheep at 6 months of age. Uninephrectomized animals had significantly elevated arterial pressure (90.1+/-1.6 compared with 77.8+/-2.9 mmHg; P<0.001), while glomerular filtration rate and renal blood flow (per g of kidney weight) were 30% lower than that of the sham animals. Total kidney weight was similar between the groups. Renal gene expression of apical NHE3 (type 3 Na+/H+ exchanger), ENaC (epithelium Na+ channel) beta and gamma subunits and basolateral Na+/K+ ATPase beta and gamma subunits were significantly elevated in uninephrectomized animals, while ENaC alpha subunit expression was reduced. Urine flow rate and sodium excretion increased in both groups in response to salt loading, but this increase in sodium excretion was delayed by approximately 90 min in the uninephrectomized animals, while total sodium output was 12% in excess of the infused load (P<0.05). In conclusion, the present study shows that animals with a congenital nephron deficit have alterations in tubular sodium channels/transporters and cannot rapidly correct for variations in sodium intake probably contributing to the development of hypertension. This suggests that people born with a nephron deficit should be monitored for early signs of renal and cardiovascular disease.

Low dose but not high dose of 17â‐estradiol prevents cardiac fibrosis in DOCA‐salt model of hypertension in rats

The current study was designed to investigate the effects of 17ß‐estradiol (E2) on cardiac remodeling. To address this issue, we evaluated cardiac fibrosis and hypertrophy in deoxycorticosterone acetate (DOCA)‐salt treated rats with chronic, six‐week administration of two different doses of E2. Female SD rats were ovariectomized bilaterally (Ovex). Hypertension was induced by subcutaneous implantation of DOCA‐pellet in uninephrectomized animals, which were later maintained on 1% saline. The rats were randomly assigned to one of the following groups: Ovex control; Ovex + DOCA; Ovex + DOCA + E2 (low dose); or Ovex + DOCA + E2 (high dose). Blood pressure measurement showed a significant increase in DOCA treated rats over a six week period, which was not altered by estrogen replacement. No difference in cardiac function was observed among the different groups when assessed using isolated rat heart Langendorff apparatus. Both doses of estrogen attenuated cardiac hypertrophy observed in the DOCA treated animals. However, when measuring cardiac fibrosis induced by DOCA treatment, only the low dose E2 therapy showed a protective effect. The high dose E2 therapy failed to exhibit anti‐fibrotic effects. These findings suggest that estrogen replacement therapy may have blood‐pressure independent cardio‐protective effects that are dose‐dependent.

Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy

Renal insufficiency is associated with the development of cardiovascular disease. This study investigated whether reduced fetal renal mass resulted in renal insufficiency, hypertension, cardiac dysfunction and whether these changes progressed with age. Fetal uninephrectomy was performed at 100-day gestation (term, 150 days) and studies performed in male sheep from 6 weeks to 24 months of age. Renal function declined with age in sham animals as demonstrated by increasing plasma creatinine levels and urinary excretion of albumin. The age-related decline in renal function was exacerbated in animals that had undergone fetal uninephrectomy. Evidence of renal insufficiency was indicated from as early as 6 weeks of age with elevations in plasma creatinine (Ptreatment < 0.001), urea (Ptreatment < 0.001) and sodium (Ptreatment < 0.05) levels in uninephrectomized lambs as compared with sham animals. At 6 months, urinary albumin excretion (P < 0.001) was increased and urinary sodium excretion (P < 0.001) decreased in the uninephrectomized animals. By 24 months, renal function had deteriorated further with significant progression of albuminuria (P(treatment x age) < 0.001). Elevation of mean arterial pressure (approximately 15 mmHg) was associated with significantly increased cardiac output, stroke volume and plasma volume at 6 months; arterial pressure (approximately 27 mmHg) had increased further in uninephrectomized animals at 24 months and was driven by increased total peripheral resistance. Cardiac functional reserve (dobutamine challenge) was reduced in uninephrectomized animals at 6 and 24 months of age (Ptreatment < 0.001), and this was associated with left ventricular enlargement (P < 0.001) and reduced fractional shortening (P < 0.01). Fetal uninephrectomy causing a reduction in nephron endowment results in an accelerated age-related decline in renal function. This is associated with an early onset of elevated blood pressure and impairments in cardiac structure and function.

Oxidative stress after uninephrectomy alters heart morphology in the apolipoprotein E −/− mouse

Even minor reduction in glomerular filtration rate accelerates atherogenesis and increases cardiovascular risk. The current study on the apolipoprotein E -/- mouse was designed to investigate whether nephron reduction by uninephrectomy causes cardiac remodeling and whether this is prevented by antioxidative treatment. We randomized apolipoprotein E -/- mice to undergo uninephrectomy or sham operation and subsequent treatment with either Tempol, Ebselen, Trandolapril, or a combination of Tempol and Trandolapril. After 12 weeks, the experiment was terminated by perfusion fixation under anesthesia. The myocardium was analyzed by morphometry. Additionally, the expression of endothelial nitric oxide synthase, transforming growth factor-beta1, vascular endothelial growth factor, flt-1, collagen I and presence of nitrotyrosine were assessed using immunohistochemistry or western blotting. Untreated uninephrectomized animals had lower capillary length density and higher volume fraction of interstitial tissue in the myocardium and bigger plaques in aorta compared with those who underwent sham operation. These changes did not develop in uninephrectomized animals treated with Tempol, Ebselen, Trandolapril, or Tempol + Trandolapril. In untreated uninephrectomized mice, the presence of nitrotyrosine and the expression of transforming growth factor-beta1, vascular endothelial growth factor, and collagen I were more marked. This was ameliorated by Tempol, Ebselen, Trandolapril, and Tempol + Trandolapril. We conclude that in the apolipoprotein E -/- mouse, even minor reduction in renal function, for example, by uninephrectomy, causes remodeling of the heart. This was ameliorated to a similar extent by antioxidants and angiotensin-converting enzyme inhibition.

Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: A dose effect study

Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model. We have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; C(cr)) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (alpha-smooth muscle actin [alpha-SMA] and vimentin expression). TMZ (5 or 10 mg/Kg) significantly increased C(cr) and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1alpha (HIF-1alpha), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the alpha-smooth muscle actin expression (alpha-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups. Collectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.

Uninephrectomy in Young Age or Chronic Salt Loading Causes Salt-Sensitive Hypertension in Adult Rats

The importance of nephron endowment and salt intake for the development of hypertension is under debate. The present study was designed to investigate whether reduced nephron number, after completion of nephrogenesis, or chronic salt loading causes renal injury and salt-sensitive hypertension in adulthood. Rats were operated at 3 weeks of age (after completed nephrogenesis) and then subjected to either normal or high-salt diets for 6 to 8 weeks. Four different experimental groups were used: sham-operated animals raised with normal-salt diet (controls) or high-salt diet (HS) and uninephrectomized animals raised with normal-salt diet (UNX) or high-salt diet (UNX+HS). In the adult animals, renal and cardiovascular functions were evaluated and blood pressure recorded telemetrically under different sodium conditions (normal, high, and low). Hypertension was present in UNX+HS (122+/-9 mm Hg), UNX (101+/-3 mm Hg), and HS (96+/-1 mm Hg) groups on normal-salt diets compared with the controls (84+/-2 mm Hg), and the blood pressure was salt sensitive (high- versus normal-salt diet; 23+/-3, 9+/-2, 7+/-2, and 1+/-1 mm Hg, respectively). The hypertensive groups (UNX+HS, UNX, and HS) had increased diuresis and reduced ability to concentrate urine. The glomerular filtration rate (milliliters per minute) in anesthetized rats was reduced in the UNX+HS (2.36+/-0.30) and UNX animals (2.00+/-0.31) compared with both HS animals (3.55+/-0.45) and controls (3.01+/-0.35). Hypertensive groups displayed reduced plasma renin concentrations during high sodium conditions and hypertrophic kidneys and hearts with various degrees of histopathologic changes. In conclusion, at a young age after completed nephrogenesis, uninephrectomy or chronic salt loading causes renal and cardiovascular injury with salt-sensitive hypertension.

Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model

Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug. Previously, we already verified its protective effect on a cold-ischemic pig kidney model by directly adding TMZ into the preservation solution (Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T. Biochem Pharmacol 66: 2241-2250, 2003; Faure JP, Petit I, Zhang K, Dutheil D, Doucet C, Favreau F, Eugene M, Goujon JM, Tillement JP, Mauco G, Vandewalle A, Hauet T. Am J Transplant 4: 495-504, 2004). In this study, we aimed to study the potential effect of TMZ pretreatment (5 mg/kg iv 24 h before WI) on the injury caused by WI for 45, 60, and 90 min and reperfusion in a WI pig kidney model. Compared with sham-operated (control) and uninephrectomized animals (UNX), TMZ pretreatment significantly reduced deleterious effects after 45 min, and particularly 60 and 90 min, of WI by improving the recovery of renal function and minimizing the inflammatory response commonly prevalent in ischemic kidney injury. Compared with controls (control group and UNX group), it was observed that 1) hypoxia-inducible factor-1 (HIF-1alpha) expression occurred earlier and with a higher intensity in the TMZ-treated groups; 2) the reduction of IRI during the first week following reperfusion was correlated with an earlier and greater expression of stathmin, which is involved in the process of tubular repair; and 3) the tubulointerstitial fibrosis was reduced, particularly after 60 and 90 min of WI. In conclusion, TMZ made the warm-ischemic kidneys more resistant to the deleterious impact of a single episode of I/R and reduced early and long-term subsequent damage.

Accelerated NaCl-induced hypertension in taurine-deficient rat: Role of renal function

Taurine modulates blood pressure and renal function. As the kidney plays a pivotal role in long-term control of arterial pressure, we tested the hypothesis that taurine-deficient rats display maladaptive renal and blood pressure responses to uninephrectomy. Control and taurine-deficient (i.e., beta-alanine-treated) rats with either one or two remaining kidneys were fed diets containing basal or high (8%) NaCl diet. Urine osmolality was greater in the taurine-deficient than controls fed a normal NaCl diet; proteinuria and blood pressure were unaffected by uninephrectomy. Following 6 weeks on an 8% NaCl diet, the uninephrectomized (UNX) animals developed significant hypertension, which was more severe in the taurine-deficient group; baroreflex function was unaffected. However, the UNX taurine-deficient rats displayed impaired ability to dispose of an acute isotonic saline volume load before a switchover to a high NaCl diet. Nonetheless, a more protracted exposure (i.e., 14 weeks) to dietary NaCl excess eliminated the blood pressure differential between the two groups; at this stage, renal excretory responses to an acute saline volume load or to atrial natriuretic peptide were similar in the two groups. Nonetheless, hypertensive taurine-deficient rats displayed greater proteinuria, although both groups excreted proteins of similar molecular weights ( approximately 15-66 kDa). Further, taurine-deficient kidney specimens displayed periarterial mononuclear cell infiltrates with strong immunoreactivity to the histiocyte marker CD68, suggestive of increased phagocytic activity. In conclusion, taurine deficiency modulates renal adaptation to combined uninephrectomy and dietary NaCl excess, resulting in an accelerated development of hypertension.

Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury

The small GTPase p21 Ras and its downstream effectors play a central role in the control of cell survival and apoptosis. We studied the effects of Ras/ERK1/2 signaling inhibition on oxidative damage in cultured renal and endothelial cells and on renal ischemia-reperfusion injury in the rat. Primary human renal tubular and human endothelial ECV304 cells underwent significant cell death when subjected to oxidative stress. This type of stress induced robustly ERK1/2 and phosphoinositide 3-kinase (PI3-kinase) signaling. Inhibition of Ras/ERK1/2 with a farnesyl transferase inhibitor, chaetomellic acid A (S-FTI), or with PD-98059, an inhibitor of MEK, a kinase upstream ERK1/2, significantly reduced the fraction of dead cells. The inhibitor of the PI3-kinase/Akt pathway, LY-294002, failed to exert a protective effect. We have translated these data in a rat model of renal ischemic injury in vivo. In uninephrectomized animals, anesthetized with pentobarbital sodium (Nembutal, 50 mg/kg i.p.), 24 h after an acute ischemic renal insult (45-min occlusion of left renal artery) a significant fraction of kidney cells succumbed to cell death resulting in renal failure [glomerular filtration rate (GFR) 0.17 +/- 0.1 vs. 0.90 +/- 0.4 ml x min(-1) x 100 g body wt(-1) in normal rats]. Rats treated with S-FTI maintained the renal function (GFR 0.50 +/- 0.1 ml x min(-1) x 100 g body wt(-1)), and the kidneys showed a significant reduction of tubular necrosis. Reduction of ischemic damage in kidney and tubular cells paralleled Ha-Ras inhibition, assayed by cytosolic translocation of the protein. These data demonstrate that inhibition of farnesylation and consequently of Ras/ERK1/2 signaling significantly reduces acute postischemic renal injury.

Antihypertensive Effect of Trigonella foenum-greacum. Seeds in Experimentally Induced Hypertension in Rats

We investigated the antihypertensive effect of a methanol extract (ME) of fenugreek seeds and its methanol fraction (MF) in deoxycorticosterone acetate (DOCA)-salt-induced and fructose-induced hypertensive rats. In the DOCA model, DOCA (15 mg/kg, twice a week; s.c.) was administered in uni-nephrectomized animals for 4 weeks. Methanol extract of fenugreek seeds (30 mg kg−1 day−1; p.o.) and its methanol fraction (15 mg kg−1 day−1; p.o.) were evaluated for their antihypertensive effect. In the fructose model, drinking water was replaced with a 10% fructose solution for 6 weeks to induce hypertension. ME (100 mg kg−1 day−1; p.o.) was assessed for its antihypertensive effect in the fructose model. After completion of the treatment schedule, blood pressure and vascular reactivity to various agonists like serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and adrenaline (Adr) were recorded in rats of both models. A dose-response curve (DRC) of 5-HT was carried out in isolated rat fundus strip of the fructose-induced hypertensive rats. Chronic administration of ME (30 mg kg−1 day−1; p.o.) and MF (15 mg kg−1 day−1; p.o.) of fenugreek seeds significantly reduced blood pressure in DOCA salt and ME (100 mg kg−1 day−1; p.o.) reduced blood pressure in fructose-induced hypertensive rats. Treatment with ME (100 mg kg−1 day−1; p.o.) in fructose model for 6 weeks shifted the DRC toward the right on rat fundus. Thus, fenugreek seeds exhibit a significant antihypertensive effect. The mechanism of action may partly involve the serotonergic antagonistic property involving the 5-HT2 receptor subtype.

Reduced renal reserve and increased cardiac output in adult female sheep uninephrectomized as fetuses

Removal of one kidney during the period of nephrogenesis in the sheep leads to offspring with elevated blood pressure and reduced glomerular filtration rate (GFR) at 6 and 12 months of age. The mechanisms underlying the hypertension and the degree of renal impairment are not known. Changes in GFR were measured in response to an infusion of amino acids and cardiac output was measured by thermal dilution in female offspring at 2 years of age in eight control (sham-operated) and seven animals that had been unilaterally nephrectomized at 100 days of gestation. Animals uninephrectomized as fetuses had significantly higher blood pressure (91 +/- 2 mm Hg) compared to control animals (86 +/- 2 mm Hg) (P < 0.05). Cardiac output was significantly higher in the uninephrectomized group (148 +/- 10 mL/kg/min) compared to the control group (124 +/- 6 mL/kg/min) (P < 0.05). Heart rate and stroke volume were similar in the two groups although both parameters tended to be higher in the uninephrectomized group. Uninephrectomized animals had a lower basal GFR (P < 0.05). An infusion of amino acids caused a significantly different response in GFR in the two groups (P < 0.01 between the groups) with the uninephrectomized animals having significantly lower GFRs during the infusion period. The increased blood pressure observed after fetal uninephrectomy is due to an increase in cardiac output. Thus, formation of a low number of nephrons in utero may predispose an individual to later renal failure and elevated blood pressure.

Acute nephrotoxicity of tacrolimus and sirolimus in renal isografts: differential intragraft expression of transforming growth factor-beta1 and alpha-smooth muscle actin.

Renal dysfunction early after kidney transplantation has multiple causes including ischemia-reperfusion (I/R) injury and drug-induced nephrotoxicity. This study assesses the acute nephrotoxicity of tacrolimus (Tac) and sirolimus (Sir) in a rat renal isograft model. Lewis renal isografts and uninephrectomized rats that did not undergo transplantation were treated with various doses of Tac (0.5-5.0 mg/kg/d) or Sir (0.5-6.5 mg/kg/d). Kidneys were examined on day 14 by routine histology and immunohistochemistry for transforming growth factor (TGF)-beta1 and alpha-smooth muscle actin (SMA). Both Tac and Sir demonstrated evidence of nephrotoxicity in the early posttransplant period including increased serum creatinine and morphologic changes in the graft including interstitial inflammation, fibrosis, and tubular vacuolization. Nephrotoxicity was most prominent in the high-dose treatment groups for both drugs and was more severe in transplanted kidneys than in uninephrectomized animals that did not undergo transplantation, suggesting an additive effect of I/R injury and drug nephrotoxicity. Both Tac and Sir increased intragraft TGF-beta1 and alpha-SMA, but there were distinct differences in the patterns of TGF-beta1 expression. Both demonstrated TGF-beta1 in tubular epithelial cells, but Sir was associated with proximal tubular TGF-beta1 localization in a bright granular pattern, whereas Tac was associated with diffuse distal tubular staining. Both Tac and Sir may be nephrotoxic in the early posttransplant period, especially at high doses and when combined with I/R injury. Immunohistochemical localization of TGF-beta1 in the tubular cells was distinctly different with each drug, suggesting possible differences in the mechanism(s) of nephrotoxicity requiring further study.

Differences in the renal dopaminergic system activity between Wistar rats from two suppliers.

Dopamine of renal origin reduces tubular sodium reabsorption and controls blood pressure. The present study evaluated renal dopaminergic activity and its response to uninephrectomy in Wistar Han rats from two suppliers, Harlan (W-H) and Charles River (W-CR). After uninephrectomy, the fractional excretion of sodium (FENa+) increased in both W-CR and W-H rats (W-CR: from 0.17 +/- 0.01 to 0.27 +/- 0.02%; W-H: from 0.39 +/- 0.04 to 0.54 +/- 0.04%, P < 0.05); however, in W-CR rats the FENa+ was lower than in W-H rats in both Sham and uninephrectomized (Unx) animals (P < 0.05). Systolic blood pressure in Unx W-CR rats was higher than in Unx W-H animals (131 +/- 3 vs. 122 +/- 2 mmHg, P < 0.05). Uninephrectomy was accompanied in W-H rats by increases in urinary levels (nmol g kidney(-1) day(-1)) of dopamine (10.3 +/- 0.5 vs. 8.3 +/- 0.7, P < 0.05) and 3,4-dihydroxyphenylacetic acid (DOPAC) (30.5 +/- 3.7 vs. 21.3 +/- 1.4, P < 0.05) and increases (P < 0.05) in maximal velocity values (Vmax in nmol mg prot(-1) 15 min(-1), 325 +/- 12 vs. 265 +/- 3) for renal aromatic L-amino acid decarboxylase (AADC), the enzyme responsible for the synthesis of renal dopamine. By contrast, in W-CR rats uninephrectomy did not change either the urinary levels of dopamine (7.1 +/- 0.5 vs. 7.6 +/- 0.7) and DOPAC (25.0 +/- 1.9 vs. 24.8 +/- 4.1) or AADC activity (Vmax 199 +/- 3 vs. 193 +/- 9). The Vmax values for renal AADC in W-CR rats were lower than those found in corresponding W-H animals. Wistar rats from different suppliers represent an important source of variability in the renal dopaminergic system activity. This may contribute to differences in sodium balance and blood pressure control in response to uninephrectomy.

Compensatory renal hypertrophy is mediated by a cell cycle-dependent mechanism

Two mechanisms exist for inducing renal proximal tubule hypertrophy. One is characterized by regulation of the G1 cell cycle kinase (cell cycle-dependent mechanism), while the other mechanism involves an imbalance between rates of protein synthesis and degradation, and occurs independently of cell cycle kinase regulation (cell cycle-independent mechanism). The present studies examined whether the compensatory proximal tubule growth following uninephrectomy is mediated by the cell cycle-dependent or -independent mechanism. Studies were done in both rats and C57Bl6 mice on tissue harvested from sham-operated or uninephrectomized animals. The magnitude of BrdU incorporation was used as the hyperplasia marker, while the proximal tubule protein: DNA ratio was used as the hypertrophy marker. Cdk4/cyclin D and cdk2/cyclin E kinase activities were assayed on renal cortex (rat studies) or isolated proximal tubules (mouse studies) using an in vitro kinase assay. In both rats and mice, compensatory proximal tubule growth was hypertrophic, not hyperplastic, evidenced by an increase in the protein:DNA ratio without a change in BrdU incorporation. In mice, cdk4/cyclin D kinase activity progressively increased between days 4 and 7, while cdk2/cyclin E kinase activity was decreased at both 4 and 7 days. In rats the development of hypertrophy was associated with an increase in cdk4/cyclin D kinase at days 4, 7, and 10, and an increase in cdk2/cyclin E kinase activity at days 2, 4, and 7. Roscovitine, a cdk2/cyclin E kinase inhibitor, inhibited cdk2/cyclin E kinase activity in both sham and nephrectomized rats; however, it did not prevent the development of proximal tubule hypertrophy. Uninephrectomy-induced compensatory proximal tubule growth is a hypertrophic form of growth that is mediated by a cell cycle-dependent mechanism.

Compensatory glomerular growth after unilateral nephrectomy is VEGF dependent.

Various growth factors and cytokines have been implicated in different forms of kidney enlargement. Vascular endothelial growth factor (VEGF) is essential for normal renal development and plays a role in diabetic glomerular enlargement. To explore a possible role for VEGF in compensatory renal changes after uninephrectomy, we examined the effect of a neutralizing VEGF-antibody (VEGF-Ab) on glomerular volume and kidney weight in mice treated for 7 days. Serum and kidney insulin-like growth factor I (IGF-I) levels were measured, since IGF-I has been implicated in the pathogenesis of compensatory renal growth, and VEGF has been suggested to be a downstream mediator of IGF-I. Placebo-treated uninephrectomized mice displayed an early transient increase in kidney IGF-I concentration and an increase in glomerular volume and kidney weight. In VEGF-Ab-treated uninephrectomized animals, increased glomerular volume was abolished, whereas renal hypertrophy was partially blocked. Furthermore, the renal effects of VEGF-Ab administration were seen without affecting the renal IGF-I levels. In conclusion, these results demonstrate that compensatory glomerular growth after uninephrectomy is VEGF dependent.

Fetal Uninephrectomy Leads to Postnatal Hypertension and Compromised Renal Function

It has been proposed that the number of nephrons an individual has may be inversely related to his or her blood pressure. In this study using female ovine fetuses, nephron number was reduced by performing a fetal uninephrectomy during the period of active nephrogenesis (100 days of gestation, term=150 days). Lambs were born at term and grew at a similar rate. At 5 months of age, ovaries were removed and the carotid artery exteriorized into a fold of skin. Blood pressure and renal function were studied at 6 and 12 months of age. At 6 months of age, uninephrectomized lambs had significantly higher mean arterial blood pressure than sham-operated lambs (89+/-2 versus 82+/-2 mm Hg, P<0.05) when measured over a 3-day period. Heart rate was not different between the groups. Urine flow rate was similar, but glomerular filtration rate was significantly lower in uninephrectomized animals (P<0.05). Urinary concentrations and excretion rates of sodium tended to be higher in uninephrectomized animals but were similar for chloride and potassium. There was no evidence of proteinuria in the uninephrectomized lambs. Similar differences were observed in blood pressure and renal function at 12 months of age. Plasma renin concentrations at this age were lower in the uninephrectomized lambs (P<0.05). An oral salt load for 10 days did not increase blood pressure significantly in either group at 12 months of age, nor were there differences in the responsiveness to graded doses of angiotensin II. These results suggest that formation of a low nephron number in utero, may result in elevated blood pressure and compromised renal function in later life.

Role of glomerular nitric oxide in glycerol-induced acute renal failure

Myoglobinuric acute renal failure remains one of the least understood clinical syndromes and the mediators involved remain obscure. The aim of the present study was to assess the role of nitric oxide in glycerol-induced acute renal failure under normal conditions and after uninephrectomy. Acute renal failure was induced in rats by injection of 50% glycerol (10 mL x kg(-1) body weight). Half of the animals were subjected to uninephrectomy two days before glycerol injection. Two days after the induction of acute renal failure, glomeruli from some animals were isolated and glomerular nitrite production was measured. Another group of animals was used for acute clearance studies. In this case, the effect of infusing either L-NAME or L-arginine was assayed. Glomerular nitrite production was significantly decreased in glycerol-induced acute renal failure. Glomeruli from uninephrectomized animals showed an increase in nitrite production, both in normal conditions and after glycerol injection, as compared with glomeruli from non-nephrectomized animals. L-NAME infusion worsened renal function in all the study groups, but more slowly in animals with glycerol-induced acute renal failure than in control rats. In uninephrectomized animals L-NAME reduced renal function more than in animals with two kidneys. In conclusion, in this model of acute renal failure the decrease in glomerular nitric oxide production plays an important role in the decrease in renal function. After uninephrectomy, an increase in glomerular nitric oxide synthesis plays a protective role against glycerol-induced acute renal failure.

Role of glomerular nitric oxide in glycerol-induced acute renal failure

Myoglobinuric acute renal failure remains one of the least understood clinical syndromes and the mediators involved remain obscure. The aim of the present study was to assess the role of nitric oxide in glycerol-induced acute renal failure under normal conditions and after uninephrectomy. Acute renal failure was induced in rats by injection of 50% glycerol (10 mL x kg(-1) body weight). Half of the animals were subjected to uninephrectomy two days before glycerol injection. Two days after the induction of acute renal failure, glomeruli from some animals were isolated and glomerular nitrite production was measured. Another group of animals was used for acute clearance studies. In this case, the effect of infusing either L-NAME or L-arginine was assayed. Glomerular nitrite production was significantly decreased in glycerol-induced acute renal failure. Glomeruli from uninephrectomized animals showed an increase in nitrite production, both in normal conditions and after glycerol injection, as compared with glomeruli from non-nephrectomized animals. L-NAME infusion worsened renal function in all the study groups, but more slowly in animals with glycerol-induced acute renal failure than in control rats. In uninephrectomized animals L-NAME reduced renal function more than in animals with two kidneys. In conclusion, in this model of acute renal failure the decrease in glomerular nitric oxide production plays an important role in the decrease in renal function. After uninephrectomy, an increase in glomerular nitric oxide synthesis plays a protective role against glycerol-induced acute renal failure.