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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.

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Inactivation of the UPII gene caused renal malfunction. (a) The standard curve of a filter paper assay for measuring the urine volume. (b) Volume per micturition. (c) Frequency of micturition. (d) Cumulative total micturition volume. (e) Blood urea nitrogen (BUN). Note the twofold increase of BUN in UPII-deficient mice (P = 0.00001) compared with wild-type mice. f–j show the urinary concentrations of uric acid (f), creatinine (g), potassium (h), sodium (i), and chloride (j). Urine and sera from 12 wild-type and 12 knockout 3-mo-old mice were pooled for these analyses. Error bars represent 1 SD.
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fig9: Inactivation of the UPII gene caused renal malfunction. (a) The standard curve of a filter paper assay for measuring the urine volume. (b) Volume per micturition. (c) Frequency of micturition. (d) Cumulative total micturition volume. (e) Blood urea nitrogen (BUN). Note the twofold increase of BUN in UPII-deficient mice (P = 0.00001) compared with wild-type mice. f–j show the urinary concentrations of uric acid (f), creatinine (g), potassium (h), sodium (i), and chloride (j). Urine and sera from 12 wild-type and 12 knockout 3-mo-old mice were pooled for these analyses. Error bars represent 1 SD.

Mentions: Using a filter paper assay, we found that UPII knockout mice had higher volume per micturition (Fig. 9 b), micturition frequency (Fig. 9 c), and total urine output (Fig. 9 d) than normal mice; no statistically significant gender differences were noted (Fig. 9, b–d). The levels of many urinary components, including uric acid, creatinine, potassium, sodium, and chloride ions, were slightly reduced (Fig. 9, f–j), possibly because of defects in mechanisms of urine concentration (Fig. 9 d). The concentration of blood urea nitrogen (BUN) almost doubled (Fig. 9 e), suggesting a compromised renal function. Interestingly, although most of the breeding pairs yielded litters that survived into adulthood, the litters of some breeding pairs (129/SvEv × Swiss Webster) reproducibly died around days 8–10 postnatally (Fig. 10, a and b). These litters were characterized by retarded growth (Fig. 10 c) and a sharp surge in the BUN level (Fig. 10 d), which suggests renal failure as a cause of death, possibly resulting from ureteral obstruction (Fig. 8, c– h) and a defective renal pelvis urothelium that normally expressed uroplakins (Fig. 10 e).


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 renal malfunction. (a) The standard curve of a filter paper assay for measuring the urine volume. (b) Volume per micturition. (c) Frequency of micturition. (d) Cumulative total micturition volume. (e) Blood urea nitrogen (BUN). Note the twofold increase of BUN in UPII-deficient mice (P = 0.00001) compared with wild-type mice. f–j show the urinary concentrations of uric acid (f), creatinine (g), potassium (h), sodium (i), and chloride (j). Urine and sera from 12 wild-type and 12 knockout 3-mo-old mice were pooled for these analyses. Error bars represent 1 SD.
© Copyright Policy
Related In: Results  -  Collection

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fig9: Inactivation of the UPII gene caused renal malfunction. (a) The standard curve of a filter paper assay for measuring the urine volume. (b) Volume per micturition. (c) Frequency of micturition. (d) Cumulative total micturition volume. (e) Blood urea nitrogen (BUN). Note the twofold increase of BUN in UPII-deficient mice (P = 0.00001) compared with wild-type mice. f–j show the urinary concentrations of uric acid (f), creatinine (g), potassium (h), sodium (i), and chloride (j). Urine and sera from 12 wild-type and 12 knockout 3-mo-old mice were pooled for these analyses. Error bars represent 1 SD.
Mentions: Using a filter paper assay, we found that UPII knockout mice had higher volume per micturition (Fig. 9 b), micturition frequency (Fig. 9 c), and total urine output (Fig. 9 d) than normal mice; no statistically significant gender differences were noted (Fig. 9, b–d). The levels of many urinary components, including uric acid, creatinine, potassium, sodium, and chloride ions, were slightly reduced (Fig. 9, f–j), possibly because of defects in mechanisms of urine concentration (Fig. 9 d). The concentration of blood urea nitrogen (BUN) almost doubled (Fig. 9 e), suggesting a compromised renal function. Interestingly, although most of the breeding pairs yielded litters that survived into adulthood, the litters of some breeding pairs (129/SvEv × Swiss Webster) reproducibly died around days 8–10 postnatally (Fig. 10, a and b). These litters were characterized by retarded growth (Fig. 10 c) and a sharp surge in the BUN level (Fig. 10 d), which suggests renal failure as a cause of death, possibly resulting from ureteral obstruction (Fig. 8, c– h) and a defective renal pelvis urothelium that normally expressed uroplakins (Fig. 10 e).

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