Limits...
Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases.

Kong XT, Deng FM, Hu P, Liang FX, Zhou G, Auerbach AB, Genieser N, Nelson PK, Robbins ES, Shapiro E, Kachar B, Sun TT - J. Cell Biol. (2004)

Bottom Line: Both knockouts also had small superficial cells, suggesting that continued fusion of uroplakin-delivering vesicles with the apical surface may contribute to umbrella cell enlargement.Both knockouts experienced vesicoureteral reflux, hydronephrosis, renal dysfunction, and, in the offspring of some breeding pairs, renal failure and neonatal death.These results highlight the functional importance of uroplakins and establish uroplakin defects as a possible cause of major urinary tract anomalies and death.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
The apical surface of mouse urothelium is covered by two-dimensional crystals (plaques) of uroplakin (UP) particles. To study uroplakin function, we ablated the mouse UPII gene. A comparison of the phenotypes of UPII- and UPIII-deficient mice yielded new insights into the mechanism of plaque formation and some fundamental features of urothelial differentiation. Although UPIII knockout yielded small plaques, UPII knockout abolished plaque formation, indicating that both uroplakin heterodimers (UPIa/II and UPIb/III or IIIb) are required for plaque assembly. Both knockouts had elevated UPIb gene expression, suggesting that this is a general response to defective plaque assembly. Both knockouts also had small superficial cells, suggesting that continued fusion of uroplakin-delivering vesicles with the apical surface may contribute to umbrella cell enlargement. Both knockouts experienced vesicoureteral reflux, hydronephrosis, renal dysfunction, and, in the offspring of some breeding pairs, renal failure and neonatal death. These results highlight the functional importance of uroplakins and establish uroplakin defects as a possible cause of major urinary tract anomalies and death.

Show MeSH

Related in: MedlinePlus

Inactivation of the UPII gene caused hydronephrosis and renal abnormalities. The kidneys of normal (a, c, and e) and UPII-deficient (b, d, and f) mice were compared in terms of their gross appearance (a and b), whole kidney section (c and d), and histological appearance (e and f). The mice used were 6 mo old for a and b, and 3 mo old for c–g. g shows a plot of renal pressure (PM − PR) versus the grade of hydronephrosis (D/T, where D and T were the diameter of the renal pelvis cavity and the thickness of the renal parenchyma, respectively). More than 100 knockout mice were studied and ∼80% of them showed various degrees of hydronephrosis. Note a lack of positive correlation between the grade of hydronephrosis and renal pressure (Pk) (t test, t = 0.177, P > 0.2), which suggests that reflux could not be a major cause of hydronephrosis. (c, e, and f) C, cortex; G, glomeruli; M, medulla; T, tubules; U, urothelium. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172608&req=5

fig7: Inactivation of the UPII gene caused hydronephrosis and renal abnormalities. The kidneys of normal (a, c, and e) and UPII-deficient (b, d, and f) mice were compared in terms of their gross appearance (a and b), whole kidney section (c and d), and histological appearance (e and f). The mice used were 6 mo old for a and b, and 3 mo old for c–g. g shows a plot of renal pressure (PM − PR) versus the grade of hydronephrosis (D/T, where D and T were the diameter of the renal pelvis cavity and the thickness of the renal parenchyma, respectively). More than 100 knockout mice were studied and ∼80% of them showed various degrees of hydronephrosis. Note a lack of positive correlation between the grade of hydronephrosis and renal pressure (Pk) (t test, t = 0.177, P > 0.2), which suggests that reflux could not be a major cause of hydronephrosis. (c, e, and f) C, cortex; G, glomeruli; M, medulla; T, tubules; U, urothelium. Bar, 50 μm.

Mentions: By administering an India ink solution into the bladders of live, anesthetized mice (Fig. 6, a and b), we determined the hydrostatic pressures at which micturition (PM) and VUR (PR) occurred. Normal mice had a PM of 28 cm of H2O pressure (Fig. 6 c), and most of them did not reflux—unless the urethra was ligated, causing outlet obstruction, and the hydrostatic pressure was increased to 40–80 cm of H2O (Fig. 6 d, WT). Although the UPII knockout mice had a normal micturition pressure of ∼24 cm of H2O (Fig. 6 c), >50% (11 out of 20) of the mice refluxed at a pressure lower than this (Fig. 6, d and e). Many of the (−/−) mice developed severe hydronephrosis with a greatly expanded renal pelvis (Fig. 7, b and d) and associated renal morphological changes (Fig. 7, a–f). To determine whether reflux caused hydronephrosis, we calculated the difference between the PM and the PR of each ureter (PK [hydrostatic pressure to the kidney] = PM − PR). For a normal mouse that had a PM of 25 cm of H2O and a PR of 50 cm, an intravesicular pressure of >25 cm of H2O would result in micturition and dissipation of pressure. However, for a UPII knockout mouse that had a PM of 25 cm of H2O but a lower PR of 18 cm of H2O, intravesicular pressures of 18–25 cm of H2O would lead to reflux, thus potentially transmitting up to 7 cm of hydrostatic pressure to the kidney (PK). We wanted to see whether this renal pressure correlated with the grade (G) of hydronephrosis—which we defined as G = D/T, where D was the internal diameter of the renal pelvis and T was the thickness of the remaining renal parenchyma (Fig. 7, c and d). If reflux were a main cause of hydronephrosis, there should have been a positive correlation between PK and G. However, we found that these two parameters were independent (P > 0.2), which suggests that reflux could not be the major etiology of hydronephrosis in this system (Fig. 7 g).


Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases.

Kong XT, Deng FM, Hu P, Liang FX, Zhou G, Auerbach AB, Genieser N, Nelson PK, Robbins ES, Shapiro E, Kachar B, Sun TT - J. Cell Biol. (2004)

Inactivation of the UPII gene caused hydronephrosis and renal abnormalities. The kidneys of normal (a, c, and e) and UPII-deficient (b, d, and f) mice were compared in terms of their gross appearance (a and b), whole kidney section (c and d), and histological appearance (e and f). The mice used were 6 mo old for a and b, and 3 mo old for c–g. g shows a plot of renal pressure (PM − PR) versus the grade of hydronephrosis (D/T, where D and T were the diameter of the renal pelvis cavity and the thickness of the renal parenchyma, respectively). More than 100 knockout mice were studied and ∼80% of them showed various degrees of hydronephrosis. Note a lack of positive correlation between the grade of hydronephrosis and renal pressure (Pk) (t test, t = 0.177, P > 0.2), which suggests that reflux could not be a major cause of hydronephrosis. (c, e, and f) C, cortex; G, glomeruli; M, medulla; T, tubules; U, urothelium. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172608&req=5

fig7: Inactivation of the UPII gene caused hydronephrosis and renal abnormalities. The kidneys of normal (a, c, and e) and UPII-deficient (b, d, and f) mice were compared in terms of their gross appearance (a and b), whole kidney section (c and d), and histological appearance (e and f). The mice used were 6 mo old for a and b, and 3 mo old for c–g. g shows a plot of renal pressure (PM − PR) versus the grade of hydronephrosis (D/T, where D and T were the diameter of the renal pelvis cavity and the thickness of the renal parenchyma, respectively). More than 100 knockout mice were studied and ∼80% of them showed various degrees of hydronephrosis. Note a lack of positive correlation between the grade of hydronephrosis and renal pressure (Pk) (t test, t = 0.177, P > 0.2), which suggests that reflux could not be a major cause of hydronephrosis. (c, e, and f) C, cortex; G, glomeruli; M, medulla; T, tubules; U, urothelium. Bar, 50 μm.
Mentions: By administering an India ink solution into the bladders of live, anesthetized mice (Fig. 6, a and b), we determined the hydrostatic pressures at which micturition (PM) and VUR (PR) occurred. Normal mice had a PM of 28 cm of H2O pressure (Fig. 6 c), and most of them did not reflux—unless the urethra was ligated, causing outlet obstruction, and the hydrostatic pressure was increased to 40–80 cm of H2O (Fig. 6 d, WT). Although the UPII knockout mice had a normal micturition pressure of ∼24 cm of H2O (Fig. 6 c), >50% (11 out of 20) of the mice refluxed at a pressure lower than this (Fig. 6, d and e). Many of the (−/−) mice developed severe hydronephrosis with a greatly expanded renal pelvis (Fig. 7, b and d) and associated renal morphological changes (Fig. 7, a–f). To determine whether reflux caused hydronephrosis, we calculated the difference between the PM and the PR of each ureter (PK [hydrostatic pressure to the kidney] = PM − PR). For a normal mouse that had a PM of 25 cm of H2O and a PR of 50 cm, an intravesicular pressure of >25 cm of H2O would result in micturition and dissipation of pressure. However, for a UPII knockout mouse that had a PM of 25 cm of H2O but a lower PR of 18 cm of H2O, intravesicular pressures of 18–25 cm of H2O would lead to reflux, thus potentially transmitting up to 7 cm of hydrostatic pressure to the kidney (PK). We wanted to see whether this renal pressure correlated with the grade (G) of hydronephrosis—which we defined as G = D/T, where D was the internal diameter of the renal pelvis and T was the thickness of the remaining renal parenchyma (Fig. 7, c and d). If reflux were a main cause of hydronephrosis, there should have been a positive correlation between PK and G. However, we found that these two parameters were independent (P > 0.2), which suggests that reflux could not be the major etiology of hydronephrosis in this system (Fig. 7 g).

Bottom Line: Both knockouts also had small superficial cells, suggesting that continued fusion of uroplakin-delivering vesicles with the apical surface may contribute to umbrella cell enlargement.Both knockouts experienced vesicoureteral reflux, hydronephrosis, renal dysfunction, and, in the offspring of some breeding pairs, renal failure and neonatal death.These results highlight the functional importance of uroplakins and establish uroplakin defects as a possible cause of major urinary tract anomalies and death.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
The apical surface of mouse urothelium is covered by two-dimensional crystals (plaques) of uroplakin (UP) particles. To study uroplakin function, we ablated the mouse UPII gene. A comparison of the phenotypes of UPII- and UPIII-deficient mice yielded new insights into the mechanism of plaque formation and some fundamental features of urothelial differentiation. Although UPIII knockout yielded small plaques, UPII knockout abolished plaque formation, indicating that both uroplakin heterodimers (UPIa/II and UPIb/III or IIIb) are required for plaque assembly. Both knockouts had elevated UPIb gene expression, suggesting that this is a general response to defective plaque assembly. Both knockouts also had small superficial cells, suggesting that continued fusion of uroplakin-delivering vesicles with the apical surface may contribute to umbrella cell enlargement. Both knockouts experienced vesicoureteral reflux, hydronephrosis, renal dysfunction, and, in the offspring of some breeding pairs, renal failure and neonatal death. These results highlight the functional importance of uroplakins and establish uroplakin defects as a possible cause of major urinary tract anomalies and death.

Show MeSH
Related in: MedlinePlus