不同种属动物尿浓缩功能和红细胞膜通透性的差异研究
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摘要
研究目的：通过研究不同种属动物肾脏解剖结构、尿浓缩能力和红细胞膜尿素通透性，以及不同蛋白质摄取量对尿浓缩能力和相关蛋白表达的调节，阐明尿素对尿浓缩能力和肾脏结构进化的作用及其机制。
技术路线：1通过对不同种属间的肾脏结构、尿浓缩功能的比较研究，分析尿素水平在动物肾脏结构和功能进化过程中的作用；2通过给大鼠饲喂不同量蛋白，研究尿素对尿浓缩功能的影响和相关蛋白的基因表达调控；3通过红细胞膜的通透性实验，对比分析不同种属间的尿素代谢水平与红细胞膜通透性的相关性。
实验方法：RT-PCR，Western-blot，Stopped-flow，免疫组化等多种方法。
主要结论：1长期高蛋白摄入量产生的高尿素水平会导致进化过程中肾脏结构和功能发生适应性改变；2高蛋白摄入量所产生的高尿素水平，显著调控尿浓缩能力和尿浓缩相关通道蛋白的表达水平；3血尿素水平差异可导致在进化过程中长期红细胞膜尿素通透性发生适应性改变，但红细胞膜对水的通透性则不受影响。
The kidney is the main excretory organ in the body, and responsible for theexcretion of various metabolic end products, as well as drugs and foreign matters intothe body. Moreover, the kidney is also an important regulatory system for the internalenvironment of the body, regulating the body fluid capacity and the excretion ofmetabolites in the body to maintain the internal homeostasis of the body. Mammaliankidney can not only excrete diluted urine but also have the ability to concentrate urine,namely, the ability to excrete the urine with higher osmotic pressure than that ofplasma. Urinary concentrating abilities of kidneys are quite different in differentspecies of animals and this difference is related to a variety of factors. In this study,various technical means of comparative physiology, comparative anatomy andmolecular biology were applied to compare the renal anatomy and physiology, bodyfluids and contents of metabolic ions in the kidneys, permeabilities of water and ureaacross red cell membrane, similarities and differences in gene expressions of ureatransport and aquaporin in10different species of animals, and analyze the correlationbetween the factors described above and the urine concentration function of kidney.The study may not only lay a foundation for further revealing the urine concentratingmechanism of mammalian kidney, but also provide the data of basic research for thescreening of kidney animal models in the study of human kidney diseases.
First, the renal physiology and anatomical structure were compared and observedin10different species of animals, including donkey, cow, sheep, pig, cat, fox, dog, rabbit,rat and mouse, and some renal physiological and anatomical indexes, such as the bodyweight and renal cortex, absolute thickness of outer medulla, inner medulla and medullarytip, and ratio of these different parts that accounted for in the kidney, were measured andcalculated. The results showed that both the physiology and anatomical structure weredifferent among the different species of animals, and the research on these differences instructure could lay the foundation for further experimental studies.
Secondly, the urine, serum, and sodium, potassium, chloride ion and ureanitrogen contents in different anatomical parts of the kidneys of the10kinds of animalswere detected in the experiment. The results showed that the differences in the serumsodium and chloride ion contents of the different species of animals were not significant different, while the differences in serum potassium and urea nitrogen contents among thespecies were found; there was no difference in contents of sodium, potassium and chlorideions in the urine among the species, but the urea nitrogen contents in the urine weresignificantly different among the species; the differences in the sodium ion contents in therenal cortex, outer medulla and inner medulla among the species were not significant, andthere was a species specificity in the sodium ion contents in the medullary tips of onlyrodents compared with those of other species; there was no difference in the potassiumcontents in the different parts of kidneys among the species, but the overall content levels ofpotassium in them were significantly higher than those in the serum; the differences inchloride ion contents in different anatomical parts of kidney were not significant among thespecies, only chloride ion contents in the medullary tips of rodents was significantly higherthan those of the other species; the overall levels of urea nitrogen in the different anatomicalparts of the kidney were comparatively lower, and only those in the medullary tips of therodents were higher and there was a significant difference compared with those of the otherspecies. The differences in the ion and urea contents in the urine of different parts ofkidneys among the different species of animals indicate the differences in the urineconcentration function, and its mechanism may be associated with multiple factors, such asrenal papillary length, the number of renal units, the percentage of long-loop nephron, theheterogeneity of nephron, the formation of the renal sinus, the degree of fusion of thecollecting duct, the formation of vascular bundle in the outer medulla, the epithelialstructure of medullary loop descending thin segment and the development of medulla.
Thirdly, in our study, the rat model with different feeding amounts of proteinswas established, in which the different feeding amounts of proteins were taken as theinfluence factors, real-time fluorescent quantitative RT-PCR, Western blot andimmunohistochemistry and other molecular biology techniques were applied to do acomprehensive research, such as the relationship between the different amounts of proteinintake and urine concentration function, the comparison on the general signs of rats fed withdifferent amount of proteins, the analysis on related detection indicators in urine and blood,and the expressions of renal urea transport and aquaporin at the gene and protein level, andthe location of their expressions. The results verified that with the increase in the feedingamount of protein to the rats, their body weights, and amounts of water intake and urineexcretion increased significantly; changes in the serum ion, serum urea nitrogen andcreatinine in the different groups of animals fed with different amounts of protein were not so obvious; however, changes in urea nitrogen, osmotic pressure, and clearances of urea andcreatinine increased with the increase of feeding amount of protein, and only the urinecreatinine concentration was opposite (reduced with the increase of feeding amount ofprotein); simultaneously, AQP2and UT-A3were found to be the important transportsresponsible for regulating the renal urine concentration function. This study may provide anscientific experimental animal model and some basic research data for the treatment ofhuman kidney diseases and the development of the drugs.
In summary, the differences in the permeability of water and urea across the redblood cell membrane among the different species of animals were compared toexplore whether the permeability was related to the urine concentration function. Thestopped-flow light scattering was employed in the experiment to detect thepermeability of urea across the red cell membrane of10different species of animals.The results showed that the red cell membranes of dogs, foxes and cats and othercarnivorous animals have a higher urea permeability, and measured Pureavalues(×10~(-5)cm/s) were5.3±0.6,3.8±0.5and2.8±0.7respectively; the values in theherbivorous animals, such as cow, donkey and sheep were lower, and0.8±0.2,0.7±0.2and1.0±0.1respectively; those in the omnivorous animals (pig) were between thoseof two species described above, and the Pureavalue was1.5±0.1; Those in the rodentanimals (mice, rats and rabbits) were between the carnivorous animals andomnivorous animals, and the Pureavalues were3.3±0.4,2.5±0.3and2.4±0.3,respectively, which presented great differences among the species. At the same timewhen Pureavalues in the different species of animals were measured, the waterpermeability was also examined. The results demonstrated that among the differentspecies of animals, the red cell membrane permeabilities of water were similar andthere was no significant difference. The above description indicates that thedifferences in the urea permeability across the erythrocyte membrane among thedifferent species of animal should be related to the long-term diet, and also closely tothe kidney’s ability to concentrate urea.
技术路线：1通过对不同种属间的肾脏结构、尿浓缩功能的比较研究，分析尿素水平在动物肾脏结构和功能进化过程中的作用；2通过给大鼠饲喂不同量蛋白，研究尿素对尿浓缩功能的影响和相关蛋白的基因表达调控；3通过红细胞膜的通透性实验，对比分析不同种属间的尿素代谢水平与红细胞膜通透性的相关性。
实验方法：RT-PCR，Western-blot，Stopped-flow，免疫组化等多种方法。
主要结论：1长期高蛋白摄入量产生的高尿素水平会导致进化过程中肾脏结构和功能发生适应性改变；2高蛋白摄入量所产生的高尿素水平，显著调控尿浓缩能力和尿浓缩相关通道蛋白的表达水平；3血尿素水平差异可导致在进化过程中长期红细胞膜尿素通透性发生适应性改变，但红细胞膜对水的通透性则不受影响。
The kidney is the main excretory organ in the body, and responsible for theexcretion of various metabolic end products, as well as drugs and foreign matters intothe body. Moreover, the kidney is also an important regulatory system for the internalenvironment of the body, regulating the body fluid capacity and the excretion ofmetabolites in the body to maintain the internal homeostasis of the body. Mammaliankidney can not only excrete diluted urine but also have the ability to concentrate urine,namely, the ability to excrete the urine with higher osmotic pressure than that ofplasma. Urinary concentrating abilities of kidneys are quite different in differentspecies of animals and this difference is related to a variety of factors. In this study,various technical means of comparative physiology, comparative anatomy andmolecular biology were applied to compare the renal anatomy and physiology, bodyfluids and contents of metabolic ions in the kidneys, permeabilities of water and ureaacross red cell membrane, similarities and differences in gene expressions of ureatransport and aquaporin in10different species of animals, and analyze the correlationbetween the factors described above and the urine concentration function of kidney.The study may not only lay a foundation for further revealing the urine concentratingmechanism of mammalian kidney, but also provide the data of basic research for thescreening of kidney animal models in the study of human kidney diseases.
First, the renal physiology and anatomical structure were compared and observedin10different species of animals, including donkey, cow, sheep, pig, cat, fox, dog, rabbit,rat and mouse, and some renal physiological and anatomical indexes, such as the bodyweight and renal cortex, absolute thickness of outer medulla, inner medulla and medullarytip, and ratio of these different parts that accounted for in the kidney, were measured andcalculated. The results showed that both the physiology and anatomical structure weredifferent among the different species of animals, and the research on these differences instructure could lay the foundation for further experimental studies.
Secondly, the urine, serum, and sodium, potassium, chloride ion and ureanitrogen contents in different anatomical parts of the kidneys of the10kinds of animalswere detected in the experiment. The results showed that the differences in the serumsodium and chloride ion contents of the different species of animals were not significant different, while the differences in serum potassium and urea nitrogen contents among thespecies were found; there was no difference in contents of sodium, potassium and chlorideions in the urine among the species, but the urea nitrogen contents in the urine weresignificantly different among the species; the differences in the sodium ion contents in therenal cortex, outer medulla and inner medulla among the species were not significant, andthere was a species specificity in the sodium ion contents in the medullary tips of onlyrodents compared with those of other species; there was no difference in the potassiumcontents in the different parts of kidneys among the species, but the overall content levels ofpotassium in them were significantly higher than those in the serum; the differences inchloride ion contents in different anatomical parts of kidney were not significant among thespecies, only chloride ion contents in the medullary tips of rodents was significantly higherthan those of the other species; the overall levels of urea nitrogen in the different anatomicalparts of the kidney were comparatively lower, and only those in the medullary tips of therodents were higher and there was a significant difference compared with those of the otherspecies. The differences in the ion and urea contents in the urine of different parts ofkidneys among the different species of animals indicate the differences in the urineconcentration function, and its mechanism may be associated with multiple factors, such asrenal papillary length, the number of renal units, the percentage of long-loop nephron, theheterogeneity of nephron, the formation of the renal sinus, the degree of fusion of thecollecting duct, the formation of vascular bundle in the outer medulla, the epithelialstructure of medullary loop descending thin segment and the development of medulla.
Thirdly, in our study, the rat model with different feeding amounts of proteinswas established, in which the different feeding amounts of proteins were taken as theinfluence factors, real-time fluorescent quantitative RT-PCR, Western blot andimmunohistochemistry and other molecular biology techniques were applied to do acomprehensive research, such as the relationship between the different amounts of proteinintake and urine concentration function, the comparison on the general signs of rats fed withdifferent amount of proteins, the analysis on related detection indicators in urine and blood,and the expressions of renal urea transport and aquaporin at the gene and protein level, andthe location of their expressions. The results verified that with the increase in the feedingamount of protein to the rats, their body weights, and amounts of water intake and urineexcretion increased significantly; changes in the serum ion, serum urea nitrogen andcreatinine in the different groups of animals fed with different amounts of protein were not so obvious; however, changes in urea nitrogen, osmotic pressure, and clearances of urea andcreatinine increased with the increase of feeding amount of protein, and only the urinecreatinine concentration was opposite (reduced with the increase of feeding amount ofprotein); simultaneously, AQP2and UT-A3were found to be the important transportsresponsible for regulating the renal urine concentration function. This study may provide anscientific experimental animal model and some basic research data for the treatment ofhuman kidney diseases and the development of the drugs.
In summary, the differences in the permeability of water and urea across the redblood cell membrane among the different species of animals were compared toexplore whether the permeability was related to the urine concentration function. Thestopped-flow light scattering was employed in the experiment to detect thepermeability of urea across the red cell membrane of10different species of animals.The results showed that the red cell membranes of dogs, foxes and cats and othercarnivorous animals have a higher urea permeability, and measured Pureavalues(×10~(-5)cm/s) were5.3±0.6,3.8±0.5and2.8±0.7respectively; the values in theherbivorous animals, such as cow, donkey and sheep were lower, and0.8±0.2,0.7±0.2and1.0±0.1respectively; those in the omnivorous animals (pig) were between thoseof two species described above, and the Pureavalue was1.5±0.1; Those in the rodentanimals (mice, rats and rabbits) were between the carnivorous animals andomnivorous animals, and the Pureavalues were3.3±0.4,2.5±0.3and2.4±0.3,respectively, which presented great differences among the species. At the same timewhen Pureavalues in the different species of animals were measured, the waterpermeability was also examined. The results demonstrated that among the differentspecies of animals, the red cell membrane permeabilities of water were similar andthere was no significant difference. The above description indicates that thedifferences in the urea permeability across the erythrocyte membrane among thedifferent species of animal should be related to the long-term diet, and also closely tothe kidney’s ability to concentrate urea.
引文
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