Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men.
Angiotensin type 2 receptor gene null mutant mice display congenital anomalies of the kidney and urinary tract (CAKUT). Various features of mouse CAKUT impressively mimic human CAKUT. Studies of the human type 2 receptor (AGTR2) gene in two independent cohorts found that a significant association exists between CAKUT and a nucleotide transition within the lariat branchpoint motif of intron 1, which perturbs AGTR2 mRNA splicing efficiency. AGTR2, therefore, has a significant ontogenic role for the kidney and urinary tract system. Studies revealed that the establishment of CAKUT is preceded by delayed apoptosis of undifferentiated mesenchymal cells surrounding the urinary tract during key ontogenic events, from the ureteral budding to the expansive growth of the kidney and ureter. (+info)
Microbiological characteristics of yeasts isolated from urinary tracts of intensive care unit patients undergoing urinary catheterization.
We studied 70 intensive care unit patients to determine the incidence of nosocomial candiduria associated with indwelling urinary catheters and to assess microbiological characteristics of the yeasts. The yeasts were isolated, 13 of 17 in urine cultures and 4 of 17 in blood cultures, and colonization had occurred 3 days after the insertion of indwelling urinary catheters. For four strains the MICs of the antifungal drugs were high. (+info)
In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.
It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia. (+info)
Effect of K+ channel openers, KRN2391 and Ki1769, and nitroglycerin on the urinary tract of rats in vivo.
The effects of KRN2391 (N-cyano-N'-(nitroxyethyl)-3-pyridine carboximidamide methane-sulfonate), which possesses ATP-sensitive potassium (K+) channel opening (KCO) activity and nitrate activity; Ki1769 (N-cyano-N'-(phenylethyl)-3-pyridinecarboximidamide methanesulfonate), which possesses only KCO activity; and nitroglycerin (NG) were determined on the motility of the ureter, urinary bladder and urethra of rats. Bladder contraction was induced by infusion of fluid into the bladder of conscious rats and recorded on a cystometrogram. KRN2391 and Ki1769 (both 0.3 mg/kg, i.v.) prolonged the micturition interval immediately after the injection, but NG (5 mg/kg, i.v.) did not. Peristaltic movement of the ureter, recorded in anesthetized rats, was inhibited by i.v. injection of KRN2391 and Ki1769 (both 0.03 mg/kg). However, when NG, NaNO2, N-nitro L-arginine methylester and methylene blue were applied directly to the ureter, no change in movement of the ureter was detected. KRN2391 (0.03 mg/kg, i.v.) and Ki1769 (0.3 mg/kg, i.v.) reduced the resistance to fluid infusion through the urethral lumen in anesthetized rats, whereas NG (0.5 mg/kg, i.v.) only reduced this resistance transiently. These results indicate that KCO activity had an inhibitory effect on the motility of the ureter, bladder and urethra. On the other hand, nitrate activity had an inhibitory effect on urethral tonus, corresponding to that induced by KCO activity. (+info)
Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract.
1. The varying profile of cell types along the muscle wall of the guinea-pig upper urinary tract was examined electrophysiologically, using intracellular microelectrodes, and morphologically, using both electron and confocal microscopy. 2. Simple 'pacemaker' oscillations (frequency of 8 min-1) of the membrane potential were recorded in both the pelvi-calyceal junction (83 % of cells) and the proximal renal pelvis (15 % of cells), but never in the distal renal pelvis or ureter. When filled with the cell marker, neurobiotin, 'pacemaker' cells were spindle shaped and approximately 160 microm in length. 3. In most cells of the ureter (100 %) and in both the proximal (75 %) and distal (89 %) renal pelvis, spontaneous action potentials (frequency of 3-5 min-1) consisted of an initial spike, followed by a number of potential oscillations superimposed on a plateau phase. When filled with neurobiotin, cells firing these 'driven' action potentials, were spindle shaped and > 250 microm in length. 4. Greater than 80 % of smooth muscle cells in the pelvi-calyceal junction were 'atypical', having < 40 % of their sectional areas occupied by loosely packed contractile filaments. Most of the smooth muscle cells in the ureter (99.7 %) and both the proximal (83 %) and distal (97.5 %) renal pelvis were of 'typical' appearance in that they contained cytoskeletal and contractile elements occupying > 60 % of cross-sectional area. 5. A third type of spontaneously discharging cell fired 'intermediate' action potentials (3-4 min-1), consisting of a single spike followed by a quiescent plateau and an abrupt repolarization. These cells were morphologically similar to interstitial cells of Cajal (ICC). However, these 'ICC-like' cells were not immuno-reactive for c-Kit, the proto-oncogene for tyrosine kinase. 6. In summary, 'atypical' smooth muscle cells were predominant in the pelvi-calyceal junction and fired 'pacemaker' potentials at a frequency significantly higher than 'driven' action potentials recorded in 'typical' smooth muscle cells throughout the renal pelvis and ureter. 'Intermediate' action potentials were recorded in 'ICC-like' cells in both the pelvi-calyceal junction and renal pelvis. We suggest that these 'ICC-like' cells act as a preferential pathway, conducting and amplifying pacemaker signals to initiate action potential discharge in the driven areas of the upper urinary tract. (+info)
How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT.
CAKUT are problems that often require surgical intervention or, in the worst case, lead to renal failure and the need for dialysis and/or renal transplantation. It is believed that these anomalies share a common genetic cause and to date there has been no good animal model with which to study these abnormalities. Although the abnormal interaction between the ureteral bud and metanephric blastema leads to renal hypodysplasia, vesicoureteral reflux, and ectopic ureters to name a few, the genetic and biochemical modulation of urinary tract development is not understood. Studies using the mouse strain mutant for angiotensin type 2 (AT2) receptors have given new insight into this mystery. The animals show defective apoptosis of undifferentiated mesenchymal cells in the area surrounding the developing kidney and urinary tract. This abnormal apoptosis may well interfere with the normal interaction between the ureteral bud and metanephric blastema resulting in CAKUT. This abnormal interaction would theoretically lead to preexisting intrinsic abnormalities of the kidney, which are programmed and take effect early in embryonic development. In the worst cases, the renal abnormalities would lead to progressive deterioration of renal function. Undoubtedly, there are more genes and biochemical modulators involved in this process other than the RAS and AT2 receptors. Our current animal model gives new and unique possibilities with which to study development of the kidney and urinary tract and ultimately seek ways of preventing an often debilitating disease process. (+info)
Obstruction of the fetal urinary tract.
Understanding the mechanisms of fetal obstructive uropathy will be essential for the specific management of the wide clinical spectrum of congenital obstructive conditions, including selecting observational therapy for mild cases and attempting to maximize renal function in severe cases. Recognition of the unique aspects of fetal renal obstruction is essential to formulate a useful research program, as the lessons of postnatal acquired obstruction are not directly transferable to congenital obstruction. Experimental studies of renal obstruction have demonstrated alterations in the developmental regulation of growth and differentiation in the fetal kidney. Depending on the gestational timing and severity of obstruction, growth may be impaired or accelerated. Similarly, patterns of altered differentiation may indicate immaturity or accelerated maturation, as well as aberrant differentiation. Concomitant with altered development, there is evidence that normal renal regulatory mechanisms, including the renin-angiotensin system and renal hemodynamics, may be affected by obstruction, possibly as compensatory responses. The mechanisms of these various alterations remain to be defined, but are likely to involve combinations of biomechanical signal transduction, growth factor expression, and responses of specific renal autoregulatory mechanisms. Fetal renal obstruction remains incompletely defined. The body of experimental evidence indicates that investigation of mechanisms regulating growth and differentiation is likely to yield important understanding of fetal renal obstruction to permit more accurate prognosis and management. Viewing fetal renal obstruction as a disorder of kidney development, with disordered growth and differentiation, suggests a definition of obstruction as a condition, that--if uncorrected--will lead to impairment in the ultimate functional potential of the kidney. Intervention should aim to maximize functional potential rather than to simply maintain the status quo. (+info)
Infertility in adult hypodactyly mice is associated with hypoplasia of distal reproductive structures.
Hypodactyly (Hoxa13(Hd)) mice have a 50-base-pair deletion in Hoxa13, and rare surviving homozygotes of both sexes are infertile. Heterozygous mutant mice are fertile; however, Hoxa13(Hd/+) females exhibit an anterior transformation of cervical tissue to a uterine stromal phenotype that is accentuated in the homozygote and occasionally includes uterine-specific glands in the transformed cervical region. The columnar-to-squamosal epithelial transition that characterizes mature cervical-vaginal tissue is positioned within uterine-like stroma rather than cervical tissue in these mutants, suggesting that this postnatal developmental transition occurs independent of the underlying stromal characteristics. Hoxa13(Hd/Hd) adult females produce apparently functional germ cells as determined by superovulation and ovarian histology, but they exhibit profound hypoplasia of the cervix and vaginal cavity. Using whole-mount in situ hybridization, we localized Hoxa13 expression to the cervical and vaginal tissues, consistent with the observed defects. In Hoxa13(Hd/Hd) males, the penian bone is severely hypoplastic and misshapen. The penian bone develops by a combination of endochondral and intramembranous ossification, but the defects observed in Hoxa13(Hd/Hd) males are limited to the region of endochondral bone formation. Our results indicate that infertility in Hypodactyly mutants is related to hypoplasia of the vaginal cavity and cervix in females and deficiency of the os penis in males. (+info)