Effect Of Unilateral Ureteral Obstruction Research Articles

The Effect of Hypertension on the Recovery of Renal Dysfunction following Reversal of Unilateral Ureteral Obstruction in the Rat.

Both ureteral obstruction (UO) and hypertension are common conditions that affect kidney functions. Hypertension and chronic kidney disease are closely associated with an overlapping and intermingled cause-and-effect relationship. The effect of hypertension on the renal dysfunction following reversible UO has not been studied previously. To study this effect, spontaneously hypertensive (G-HT, n = 10) and normotensive Wistar (G-NT, n = 10) rats underwent 48-h reversible left unilateral UO (UUO), and the effect of UUO was studied 96 h following UUO reversal. The glomerular filtration rate, renal blood flow, and renal tubular functions such as the fractional excretion of sodium in the post-obstructed left kidney (POK) in both groups were significantly altered compared with the non-obstructed right kidney (NOK). However, the alterations in the G-HT were significantly more exaggerated when compared with the G-NT. Similar findings were observed with the histological features, gene expression of kidney injury markers, pro-inflammatory, pro-fibrotic and pro-apoptotic cytokines, and pro-collagen, as well as tissue levels of apoptotic markers. We conclude that hypertension has significantly exaggerated the alterations in renal functions and other parameters of renal injury associated with UUO.

MP05-17 INFLAMMATORY CYTOKINES PROMOTE FIBROSIS IN OBSTRUCTED URETERS

You have accessJournal of UrologyCME1 May 2022MP05-17 INFLAMMATORY CYTOKINES PROMOTE FIBROSIS IN OBSTRUCTED URETERS Alina Reicherz, Felipe Eltit, Khaled Almutairi, Roman Herout, Michael Cox, Ben Chew, and Dirk Lange Alina ReicherzAlina Reicherz More articles by this author , Felipe EltitFelipe Eltit More articles by this author , Khaled AlmutairiKhaled Almutairi More articles by this author , Roman HeroutRoman Herout More articles by this author , Michael CoxMichael Cox More articles by this author , Ben ChewBen Chew More articles by this author , and Dirk LangeDirk Lange More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002522.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To better understand the impact of ureteral obstruction on ureteral tissue, triggered inflammatory response and fibrotic changes. METHODS: Twenty-four murine ureters were obstructed unilaterally for 7 days. 11 mice were euthanized after clamp removal; 13 mice were recovered after clamp removal for 8 days. Unobstructed ureters from 9 mice served as controls. Peristalsis was determined by magnified observation, and hydronephrosis was evaluated by ultrasound. Ureters were harvested, and ureteral tissue was evaluated histologically. 44 cytokines, chemokines and 5 matrix-metalloproteases were quantified using Multiplex panels (Eve Technologies). RESULTS: We observed grade 4 hydronephrosis in all obstructed mice. Similarly, peristalsis was reduced significantly and did not recover fully during the 8 days recovery after clamp removal. Histologically, obstructed ureters showed urothelial changes, fibrosis of lamina propria and adventitia, and thickened muscular layers. Collagen fibres infiltrate the muscular layer of all obstructed ureters but are not observed in non-obstructed ureters. Inflammatory changes in the connective tissue of obstructed ureters are characterized by hyperaemia and leukocytes. Through unsupervised hierarchical clustering, we demonstrate a different cytokine pattern between the groups in which all samples cluster. The highest similarities are observed between the control group and the group of contralateral ureters (ipsilateral side obstructed for 7 days). The group of ureters obstructed for 7 days, and their contralateral ureters are the most different. Consistently, matrix-metalloproteases (MMP-2, MMP-3 and MMP-8) increased significantly after obstruction. Cytokines from T-cell recruitment (IL-16, TARC, MDC) were increased in the obstructed ureter. In addition, the unobstructed, contralateral ureters showed significantly increased levels of cytokines of T-helper cells (Th1: IFN-γ, IL-2, IL-12p40, TNFα; Th2: IL-9, IL-10, IL-13). CONCLUSIONS: Ureteral obstruction triggered a pro-inflammatory response and subsequent fibrosis. These changes seem to impair long-term ureteral functionality. Strikingly, the increase of pro-inflammatory cytokines in the contralateral ureters indicates a systemic effect of unilateral ureteral obstruction. Source of Funding: Alina Reicherz (RE 4611/2-1) is funded by the German Research Foundation (DFG) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e74 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alina Reicherz More articles by this author Felipe Eltit More articles by this author Khaled Almutairi More articles by this author Roman Herout More articles by this author Michael Cox More articles by this author Ben Chew More articles by this author Dirk Lange More articles by this author Expand All Advertisement PDF DownloadLoading ...

UT-A1/A3 knockout mice show reduced fibrosis following unilateral ureteral obstruction.

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-β, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-β, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson's trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.

Upregulation of p16, Bax and Bcl-2 mRNA Expression Associated with Epithelial Apoptosis and Myofibroblast Proliferation in Kidney Fibrosis Model in Mice.

BackgroundCellular senescence may play a role in the development of kidney fibrosis, but its specific association with apoptosis or proliferation have yet to be determined.ObjectivesThis study aims to determine the effects of unilateral ureteral obstruction (UUO) on proliferation, cellular senescence and apoptosis in kidney fibrosis.MethodsA unilateral ureteral obstruction (UUO) procedure was performed to induce kidney fibrosis in 24 Swiss mice (3 months old, 30 g–40 g). Mice were sacrificed on day 3 (UUO3, n = 6), day 7 (UUO7, n = 6) and day 14 (UUO14, n = 6). Sham operation (SO) procedures were performed on the control group. The expression of Bcl-2, p16 and Bax mRNA was quantified with reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical (IHC) staining with anti-Bcl-2 and p53 antibodies was used to determine the localisation of proliferation and apoptosis. Data were analysed using one-way ANOVA followed by a post hoc least significant difference (LSD) test (P < 0.05)ResultsRT-PCR analysis showed higher mRNA expression of Bcl-2, p16 and Bax in the UUO groups compared with SO group (P < 0.05). Immunostaining showed that Bcl-2 and p53 expression in tubular epithelium in the UUO groups, except Bcl-2 expression was found in interstitial areas of UUO14 group.ConclusionSenescence in UUO might be associated with epithelial apoptosis and myofibroblast proliferation.

Unilateral ureteral obstruction causes gut microbial dysbiosis and metabolome disorders contributing to tubulointerstitial fibrosis

Chronic kidney disease (CKD) increases the risk and prevalence of cardiovascular disease (CVD) morbidity and mortality. Recent studies have revealed marked changes in the composition of the microbiome and the metabolome and their potential influence in renal disease and CVD via the accumulation of microbial-derived uremic toxins. However, the effect of unilateral ureteral obstruction (UUO) on the gut microbiome and circulating metabolites is unknown. Male Sprague-Dawley rats were randomized to UUO and sham-operated control groups. Renal histology, colonic microbiota, and plasma metabolites were examined two weeks later. We employed 16S rRNA sequence and untargeted metabolomic analyses to explore the changes in colonic microbiota and plasma metabolites and their relationship with tubulointerstitial fibrosis (TIF). The UUO rats exhibited tubular atrophy and dilatation, interstitial fibrosis and inflammatory cell infiltration in the obstructed kidney. UUO rats showed significant colonic enrichment and depletion of genera. Significant differences were identified in 219 plasma metabolites involved in lipid, amino acid, and bile acid metabolism, which were consistent with gut microbiota-related metabolism. Interestingly, tryptophan and its metabolites kynurenine, 5-hydroxytryptophan and 5-hydroxytryptamine levels, which were linked with TIF, correlated with nine specific genera. Plasma tryptophan level was positively correlated with Clostridium IV,Turicibacter, Pseudomonas and Lactobacillales, and negatively correlated with Oscillibacter, Blautia, and Intestinimonas, which possess the genes encoding tryptophan synthase (K16187), indoleamine 2,3-dioxygenase (K00463) and tryptophan 2,3-dioxygenase (K00453) and their corresponding enzymes (EC:1.13.11.52 and EC:1.13.11.11) that exacerbate TIF. In conclusion, UUO results in profound changes in the gut microbiome and circulating metabolites, events that contribute to the pathogenesis of inflammation and TIF.

Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice.

Previous studies have suggested that Klotho provides reno-protection against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis (RTF). Because the existing studies are mainly performed using heterozygous Klotho mutant (HT) mice, we focused on the effect of UUO on homozygous Klotho mutant (kl/kl) mice. UUO kidneys from HT mice showed a significantly higher level of RTF and TGF-β/Smad3 signaling than wild-type (WT) mice, whereas both were greatly suppressed in kl/kl mice. Primary proximal tubular epithelial culture cells isolated from kl/kl mice showed no suppression in TGF-β1-induced epithelial mesenchymal transition (EMT) compared to those from HT mice. In the renal epithelial cell line NRK52E, a large amount of inorganic phosphate (Pi), FGF23, or calcitriol was added to the medium to mimic the in vivo homeostasis of kl/kl mice. Neither Pi nor FGF23 antagonized TGF-β1-induced EMT. In contrast, calcitriol ameliorated TGF-β1-induced EMT in a dose dependent manner. A vitamin D3-deficient diet normalized the serum 1,25 (OH)2 vitamin D3 level in kl/kl mice and enhanced UUO-induced RTF and TGF-β/Smad3 signaling. In conclusion, the alleviation of UUO-induced RTF in kl/kl mice was due to the TGF-β1 signaling suppression caused by an elevated serum 1, 25(OH)2 vitamin D3.

Glomerular sclerosis is prevented during urinary tract obstruction due to podocyte protection

Urine outflow obstruction activates a variety of profibrotic factors, including the intrarenal renin-angiotensin system. However, the obstruction also nullifies the transmural hydraulic pressure difference across the glomerular capillary wall, an established inducer of glomerulosclerosis. In the present study, we investigated whether, and by what mechanism, urine outflow obstruction affects the process of progressive glomerulosclerosis. For this purpose, we tested the effect of unilateral ureteral obstruction (UUO) of 7 days duration in two distinct mouse models of glomerulosclerosis. In the human immunodeficiency virus (HIV) nephropathy model, where HIV-1 genes are selectively expressed in podocytes and develop progressive podocyte damage and glomerulosclerosis, UUO protected against sclerosis with preservation of podocytes morphologically and immunohistochemically. In contrast, the nonobstructed contralateral kidneys of these mice, as well as sham-operated HIV-1 mouse kidneys, developed severe podocyte injury and glomerulosclerosis. The protection against glomerulosclerosis imparted by ureteral obstruction was also documented in the NEP25 model of podocyte injury, in which a single injection of immunotoxin, LMB2, triggers selective podocyte injury followed by glomerulosclerosis, both of which were protected by UUO. Notably, intervention with an angiotensin II type 1 receptor antagonist provided only a partial protective effect in each of the models. These results demonstrate that urine outflow obstruction protects the glomerulus from progressive sclerosis. The results further reveal that this protection occurs at a very early stage of the pathologic process, namely, damage of podocytes.

Propagation of the Electrical Impulse in Reversible Unilateral Ureteral Obstruction as Determined at High Electrophysiological Resolution

We investigated the propagation of electrical impulses in a reversible, complete or partial unilateral ureteral obstruction model in vivo. In Wistar rats the left mid ureter was completely (8) or partially (7) occluded and released after 24 hours. We recorded electrical activity of the left and right ureter before, during and after obstruction at different stages up to 2 weeks after obstruction using a high resolution, 64 extracellular electrode probe. Complete obstruction in the left proximal ureter caused an immediate increase in frequency from a mean ± SEM of 14.8 ± 1.3 to 18.6 ± 1.7 per minute (p <0.05), followed by a 1.4 ± 0.9 per minute decrease (p <0.001). Within the first 2 days after reversal velocity gradually decreased from 1.82 ± 0.12 to 0.79 ± 0.17 cm per second (p <0.001). Release of obstruction gradually restored frequency and velocity, which returned to baseline at 2 weeks. Generally the alterations in rats with complete and partial obstruction were similar but they were less marked in those with partial obstruction. Distal to the obstruction site the impulses disappeared (38%) or propagated retrograde (43%) at some stage in the post-obstruction period. These abnormal impulse propagations also gradually disappeared in the post-obstruction stage. After complete or partial ureteral obstruction there were immediate, significant changes in the propagation of electrical impulses in the proximal and distal left ureter, which were generally less marked after partial than after complete obstruction. Reversal of obstruction resulted in the gradual disappearance of this abnormality in 2 weeks.

Effect of Unilateral Ureteral Obstruction and Anti-angiotensin II Treatment on Renal Tubule and Interstitial Cell Apoptosis in Rats

To investigate the effects of angiotensin-converting enzyme inhibitor (cilazapril) and angiotensin II type I receptor antagonist (losartan) on tubular and interstitial cell apoptosis and caspase-3 activity in rats with obstructive nephropathy after unilateral ureteral obstruction. Rats with unilateral obstructive nephropathy and sham-operated rats were treated with cilazapril, losartan, or the vehicle (water). Tubular and interstitial cell apoptosis was detected morphologically on hematoxylin and eosin-stained renal specimens and by the terminal deoxynucleotidyl transferase-mediated nick end-labeling. Caspase-3 activity in whole-kidney tissue homogenates was measured colorimetrically. After unilateral ureter ligation, there was a significant increase in the number of apoptotic tubular and interstitial cells in the obstructed kidney (P=0.049 and P=0.036, respectively, vs sham-operated rats, 10 days after ligation). In rats with unilateral obstructive nephropathy, neither cilazapril nor losartan had an effect on tubular cell apoptosis. However, cilazapril caused a significant increase in the number of renal apoptotic interstitial cells (P=0.019). Caspase-3 activity was not significantly different in rats with unilateral obstructive nephropathy than in sham-operated rats. Rats with unilateral obstructive nephropathy had increased apoptosis of tubular and interstitial cells in comparison with sham-operated rats. Neither cilazapril nor losartan had an effect on tubular cell apoptosis, and cilazapril even increased interstitial cell apoptosis.

698: Effect of Unilateral Ureteral Obstruction (UUO) on the Transduction of Green Fluorescent Protein (GFP) Using Adeno-Associated Viral Vector in Kidney

698: Effect of Unilateral Ureteral Obstruction (UUO) on the Transduction of Green Fluorescent Protein (GFP) Using Adeno-Associated Viral Vector in Kidney

Effect of UUO on D1aR expression reveals a link among dopamine, transforming growth factor-beta, and nitric oxide.

Interactions between transforming growth factor-beta (TGF-beta) and nitric oxide (NO) are important in the pathophysiology of unilateral ureteral obstruction (UUO). Dopamine (DA) is a vasoactive renal mediator active at the D(1A) receptor (D(1A)R), which has not been studied in UUO; therefore, we examined the interactions among DA, TGF-beta, and NO in UUO. In vivo, UUO was carried out in rats with or without concurrent treatment with 1D11, a monoclonal antibody to TGF-beta, for 14 days. In vitro, NRK-52E cells (normal rat kidney tubules) were treated with DA, and NO and TGF-beta release were examined. UUO resulted in a 70% decrease in the expression of renal D(1A)R, confirmed by both Western blot analysis and immunohistochemistry. 1D11 treatment restored expression to 60% of control values. DA treatment decreased NRK-52E release of TGF-beta by 80%; conversely, DA significantly increased NO release from NRK-52E cells. These results suggest that DA modulates the release of cytokines, which are involved in the fibrotic and apoptotic sequelae of UUO, and that these effects are independent of DA's known vasoactive properties.

The effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule and intesstitial cell apoptosis in rats

The effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule and intesstitial cell apoptosis in rats

Free insulin-like growth factor-1 and unilateral complete ureteral obstruction in the rat

Objectives. To determine the effect of unilateral ureteral obstruction on renal free insulin-like growth factor-1 (IGF-1) content in the kidneys and the possible role of free IGF-1 in compensatory growth in the nonobstructed kidney in an experimental model. Methods. The content of free IGF-1 and total protein in the obstructed and nonobstructed kidneys were measured 7 days after unilateral ureteral obstruction. The weights of the kidneys were also determined. The results were compared with those of the sham-operated animals. Results. The mean renal free IGF-1 level of the obstructed kidneys was significantly lower than the mean renal free IGF-1 level of the sham-operated kidneys ( P = 0.03), and the mean renal free IGF-1 level of the nonobstructed kidneys was significantly higher than the mean renal free IGF-1 level of the sham-operated kidneys ( P <0.0001). The serum free IGF-1 levels in the two groups were not different. The mean weight of the obstructed and nonobstructed kidneys was significantly higher than those of the sham-operated kidneys (1.49 ± 0.09 and 1.03 ± 0.03 versus 0.88 ± 0.02 g, P <0.0001 and P = 0.006, respectively). The obstructed kidneys had significantly lower mean protein content than the nonobstructed kidneys and had significantly higher mean protein content than the sham-operated kidneys ( P <0.0001 and P = 0.0004, respectively). Conclusions. Our results reveal that compensatory renal growth is driven by a rise in the free IGF-1 concentration after unilateral ureteral obstruction.

Renal tubular apoptosis after complete ureteral obstruction in the presence of hyperoxaluria.

Hyperoxaluria is a well-known cause of renal stone disease and in vitro studies have shown that oxalate crystals have a stimulatory effect on apoptosis of renal tubular epithelial cells. Total and partial ureteral obstruction also have an accelerating effect on apoptosis of renal tubular epithelial cells. The aim of the present study was to investigate the apoptotic effect of unilateral ureteral obstruction in the presence of hyperoxaluria on the rat kidney. Twenty-eight male Wistar rats were divided into four groups, with seven rats in each. The groups were named G1 (control), G2 (hyperoxaluric), G3 (obstructive) and G4 (hyperoxaluric + obstructive). G2 and G4 rats were given 1% ethylene glycol (a precursor for oxalates) in their drinking water. G1 and G2 rats underwent sham operation, while left proximal ureteral ligation with a 5-zero silk suture was performed on G3 and G4 animals. The rats were sacrificed 2 weeks after the operation; left nephrectomy was then performed. We searched for the apoptotic cells by direct immuno-peroxidase detection of digoxigenin-labeled genomic DNA. The mean +/- SD values of the apoptotic cell count was 0.86+/-0.90 in G1 and 4.33+/-3.81 in G2. The values for G3 and G4 were 30.17+/-16.85 and 302.67+/-184.45, respectively. We found a statistically significant difference between all groups (P < 0.001). When compared with the control group (G1), the mean apoptotic cell count was fivefold that of G2 and 35- and 351-fold those of G3 and G4, respectively. Our study demonstrated that hyperoxaluria with complete ureteral obstruction induces an excessive level of apoptosis, which is responsible for renal damage, and that ureteral obstruction is a more important factor for apoptosis than hyperoxaluria. Considering these data, we also believe that research studies for medical preventive measures must be considered for patients with ureteral obstruction and/or hyperoxaluria.

Long-term renal effects of unilateral ureteral obstruction and the role of endothelin

Angiotensin II (Ang II) and endothelin (ET) are involved in the alteration of renal function in unilateral ureteral obstruction (UUO). The renal response to Ang II following the reversal of a 24-hour UUO and the effect of ET blockade by bosentan during the time of obstruction were investigated. Following blockade of the endogenous production of Ang II by captopril, the renal response to Ang II was studied in rats 15 to 18 days after a 24-hour UUO (N = 10) or a sham operation (N = 9) both with (N = 10) and without (N = 8) bosentan treatment in the periobstruction period. Similar studies were performed in another group (N = 9) two months following the reversal of obstruction. In the sham-operated group, Ang II reduced renal blood flow (RBF) by 42 +/- 9% (P < 0.01), glomerular filtration rate (GFR) by 30 +/- 8% (P < 0.01), urine volume (UV) by 44 +/- 9% (P < 0.001), and absolute (UNaV) and fractional sodium excretion (FENa) by 52 +/- 9% (P < 0.001) and 33 +/- 9% (P = 0.054), respectively. In the previously obstructed kidney, Ang II did not change RBF but increased GFR by 106 +/- 40% (P < 0.01), UV by 75 +/- 21% (P < 0.001), UNaV by 190 +/- 60% (P < 0.001), and FENa by 40 +/- 13% (P < 0.05). Bosentan treatment in the obstructed group prevented these Ang II-induced effects and did not have any effect on the sham-operated kidney. Two months following reversal of the obstruction, the response of the kidney was similar to that of the control kidney. Twenty-four-hour UUO results in a temporary abnormality in the renal response to Ang II, which is due, in part, to the actions of ET at the time of obstruction.

Molecular and cellular pathophysiology of obstructive nephropathy.

Congenital obstructive nephropathy remains one of the most-important causes of renal insufficiency in children. This review focuses on the unique interactions that result from urinary tract obstruction during the period of renal development in the neonatal rodent. Following unilateral ureteral obstruction (UUO), growth of the obstructed kidney is impaired and compensatory growth by the intact opposite kidney is related directly to the duration of obstruction. Development of the renal vasculature is delayed by UUO, and the activity of the intrarenal renin-angiotensin system is enhanced throughout the period of obstruction. Glomerular maturation is also delayed by UUO, and nephrogenesis is permanently impaired. The effects of UUO on the developing tubule are also profound, with a suppression of proliferation, stimulation of apoptosis, and the maintenance of an immature phenotype by tubular epithelial cells. Expression of tubular epidermal growth factor is suppressed and transforming growth factor-beta1 and clusterin are increased. Maturation of interstitial fibroblasts is delayed, with progression of tubular atrophy and interstitial fibrosis resulting in part from continued activation of the renin-angiotensin system and oxygen radicals. Future efforts to prevent the consequences of congenital urinary tract obstruction must account for the dual effects of obstruction: interference with normal renal development and progression of irreversible tubulointerstitial injury.

Ureteral obstruction in the neonatal guinea pig: Interaction of sympathetic nerves and angiotensin

The contribution of sympathetic nerves to the hemodynamic effects of unilateral ureteral obstruction (UUO) was investigated in the neonatal guinea pig. The left ureter was partially constricted (or sham-operated) at birth, and sympathetic innervation was inhibited by guanethidine and compared with saline vehicle-treated animals. At 15-20 days of age, blood pressure, cardiac output, total vascular resistance (TVR), renal blood flow, and renal vascular resistance (RVR) were determined before and after infusion of enalapril. UUO reduced cardiac output, increased TVR, and increased RVR of the ipsilateral kidney, whereas guanethidine treatment had no additional effects. Enalapril decreased RVR only in obstructed kidneys and not in intact opposite kidneys of animals with UUO. This was not affected by guanethidine administration. In contrast, enalapril decreased RVR only in guanethidine-treated (but not saline-treated) sham-operated guinea pigs. Therefore, UUO increases angiotensin-dependent vascular tone of the ipsilateral kidney independent of renal innervation. However, UUO decreases angiotensin-mediated vascular tone of the contralateral kidney, an effect unmasked by sympathectomy.

Urinary Obstruction Reduces Glomerulogenesis in the Developing Kidney: A Model in the Rabbit

To study the effect of unilateral ureteral obstruction upon the development of the kidney a fetal rabbit model was developed. A total of 27 rabbits underwent ureteral ligation in utero (24 days after conception) and 34 underwent ureteral ligation at term (30 days after conception). Two rabbits undergoing in utero ureteral ligation underwent decompression at term. Fetal development was evaluated by glomerular counts of mid sagittal sections of the kidney and compared to that of 67 normal rabbits, 43 littermates of rabbits undergoing surgery, 12 rabbits with missed ligation of the ureter and 4 whose ureters were ligated after the period of nephrogenesis had ended (57 days after conception).In the normal rabbit term occurred at 31 days after conception but nephrogenesis continued until 48 days when the cortical glomerular count reached approximately 650. Ligation of the ureter at 24 days led to a rapid decrease in cortical glomerular counts in the obstructed kidney but glomeruli developing within the nephrogenic cap were more resistant to the effects of the obstruction. Glomerular counts in the nonobstructed kidney were similar to those of littermates. Ligation of the ureter at 30 days produced similar findings. All operated fetuses and their littermates showed glomerular counts less than that of normal animals of the same age. In the 2 fetuses who underwent ureteral ligation at 24 days after conception and decompression at 30 days after conception sacrifice at 42 days after conception revealed that glomerular counts that had been reduced by 95 per cent by the obstruction showed 80 per cent recovery after decompression.It appears that renal development can be quantified by glomerular counts in the rabbit. Obstruction during fetal development reduces these counts while in a limited sample decompression of the obstructed kidney partially restores them. This model appears to be suitable for the study of the effects of fetal surgery upon renal function.

Extratubular Tamm-Horsfall protein deposits induced by ureteral obstruction in mice

The effects of unilateral ureteral obstruction were studied in mice. Obstruction for 24 hr led to the formation of extratubular Tamm-Horsfall protein (TH) aggregates within the renal interstitium and at the base of distal convoluted tubular (DCT) cells. These DCT deposits were shown by ultrastructural analysis to be entirely extracellular. They had the fibrillar substructure characteristic of TH and had not been seen after urinary obstruction in other species. As a consequence of retrograde flow of urine to glomeruli, obstruction also caused TH aggregates to form within Bowman's spaces. These glomerular casts of TH were detected throughout the 3-week period of study after the release of unilateral obstruction. High serum titers of IgG antibodies to TH developed in mice intradermally immunized with TH but were not observed after obstruction alone. Circulating anti-TH antibodies combined with TH present on the basal surfaces of the thick ascending limb of the loop of Henle cells and DCT cells to form immune complexes in situ. Interstitial inflammation in the areas surrounding subepithelial tubular immune deposits was not present in the kidneys of immunized mice and was not selectively induced by temporary obstruction. However, foci of inflammation were seen in all obstructed kidneys. At later times, inflammatory foci in previously obstructed kidneys were associated with progressive scarring, primarily in polar regions. The location and severity of these changes within kidneys produced by obstruction in immunized mice did not differ from those in unimmunized mice. The titers of anti-TH antibodies in immunized mice were not enhanced or depressed as a consequence of unilateral ureteral obstruction. These studies demonstrate that complete obstruction of urinary flow in the mouse for periods as short as 24 hr may lead to progressive segmental renal scarring. These studies further indicate that increasing the quantities of extracellular TH by obstruction does not facilitate inflammatory responses to TH immune complexes formed in situ. While exposure of renal tissue to highly toxic components of extravasated urine may play a crucial role in inflammatory responses, autoimmunity to TH was not implicated as a contributing factor by the present studies in mice.

Effect of unilateral ureteral obstruction on metabolism of renal lipids in the rat.

The metabolism of lipids in the cortex and inner medulla of control and experimental kidneys of rats with unilateral ureteral obstruction (UUO) was studied in vitro. A marked increase in the tissue triglyceride content was noted after 24 h of obstruction in the experimental kidney compared with the contralateral kidney of rats with UUO and normal kidneys from sham-operated rats. A decrease in total phospholipid content was seen in the experimental kidney after 24 h of obstruction. The incorporation of [1-14C]oleic acid or [14C]arachidonic acid into tissue triglycerides was significantly increased in the cortex and medulla of the experimental kidney of rats with UUO compared with either the contralateral kidney of the same animals or kidneys from sham-operated rats. The oxidation of [1-14C]oleic acid to 14CO2 and the incorporation of [14C]arachidonic acid into tissue phospholipids or free fatty acids were significantly lower in the experimental kidney of rats with UUO. The results strongly suggest an increase in the net synthetic rate of triglycerides in the experimental kidney of UUO rats. This increase may be related to both a decrease in fatty acid oxidation and an increased release of fatty acids from phospholipids presumably due to increased phospholipase activity.