Paraxial mesoderm contributes stromal cells to the developing kidney

The development of most, if not all, tubular organs is dependent on signaling between epithelial and stromal progenitor populations. Most often, these lineages derive from different germ layers that are specified during gastrulation, well in advance of organ condensation. Thus, one of the first stages of organogenesis is the integration of distinct progenitor populations into a single embryonic rudiment. In contrast, the stromal and epithelial lineages controlling renal development are both believed to derive from the intermediate mesoderm and to be specified as the kidney develops. In this study we directly analyzed the lineage of renal epithelia and stroma in the developing chick embryo using two independent fate mapping techniques. Results of these experiments confirm the hypothesis that nephron epithelia derive from the intermediate mesoderm. Most importantly, we discovered that large populations of renal stroma originate in the paraxial mesoderm. Collectively, these studies suggest that the signals that subdivide mesoderm into intermediate and paraxial domains may play a role in specifying nephron epithelia and a renal stromal lineage. In addition, these fate mapping data indicate that renal development, like the development of all other tubular organs, is dependent on the integration of progenitors from different embryonic tissues into a single rudiment.     

Secretion of lipoprotein particles by the cells of the kidney proximal segment in the migrating arctic lamprey,Lampetra japonica

Summary The cells of the kidney proximal segment of the migrating arctic lamprey, Lampetra japonica, contain particles of the same size, electron-density and intracellular location as particles identified by others as very low-density lipoproteins (VLDL) in the liver and intestine of teleost fishes and lampreys. These particles are synthesized within the cisternae of the smooth endoplasmic reticulum and elements of the Golgi complex. They are transferred to the lateral intercellular space and lamina propria by way of the Golgi vesicles and an intracellular channel system. Some particles are discharged into the lumina of the sinusoidal capillaries of the lamina propria. Although the physiological role of lipoprotein secretion in the renal proximal segment cells is unknown, the present observations provide morphological evidence that the kidney of the arctic lampreys synthesizes lipoproteins and releases them into the circulation at the time when they are undertaking their anadromous migration.     

Differential expression pattern of protein ARVCF in nephron segments of human and mouse kidney

The protein ARVCF is a member of the p120 subfamily of armadillo proteins whose members have been described to occur in junction-bound and non-junction-bound forms. Studies on ARVCF were constrained because the endogenous protein was difficult to detect with the available reagents. We have generated novel monoclonal and polyclonal antibodies usable for biochemical and localization studies. By systematic immunohistochemical analysis of various tissues protein ARVCF is prominently detected in mouse, bovine and human kidney. Using antibodies against specific markers of nephron segments protein ARVCF is localized in proximal tubules according to double label immunofluorescence. Besides its occurrence in proximal tubules of adult kidney and in renal cell carcinoma derived from proximal tubules ARVCF is also detected in maturing nephrons in early mouse developmental stages such as, for example, 15 days of gestation (E15). Immunoblotting of total extracts of cultured cells of renal origin showed that ARVCF is detected in all human and murine cultured cells analyzed. Upon immunolocalization ARVCF is mostly detected in the cytoplasm occurring in a fine granular form. This prominent cytoplasmic localization of ARVCF in cultured cells and its occurrence in proximal tubules implies an involvement of ARVCF in specific functional processes of proximal tubules of kidney. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Zebrafish mutations affecting cilia motility share similar cystic phenotypes and suggest a mechanism of cyst formation that differs from pkd2 morphants

Zebrafish are an attractive model for studying the earliest cellular defects occurring during renal cyst formation because its kidney (the pronephros) is simple and genes that cause cystic kidney diseases (CKD) in humans, cause pronephric dilations in zebrafish. By comparing phenotypes in three different mutants, locke, swt and kurly, we find that dilations occur prior to 48 hpf in the medial tubules, a location similar to where cysts form in some mammalian diseases. We demonstrate that the first observable phenotypes associated with dilation include cilia motility and luminal remodeling defects. Importantly, we show that some phenotypes common to human CKD, such as an increased number of cells, are secondary consequences of dilation. Despite having differences in cilia motility, locke, swt and kurly share similar cystic phenotypes, suggesting that they function in a common pathway. To begin to understand the molecular mechanisms involved in cyst formation, we have cloned the swt mutation and find that it encodes a novel leucine rich repeat containing protein (LRRC50), which is thought to function in correct dynein assembly in cilia. Finally, we show that knock-down of polycystic kidney disease 2 (pkd2) specifically causes glomerular cysts and does not affect cilia motility, suggesting multiple mechanisms exist for cyst formation.     

The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage

We previously determined that Notch2, and not Notch1, was required for forming proximal nephron segments. The dominance of Notch2 may be conserved in humans, since Notch2 mutations occur in Alagille syndrome (ALGS) 2 patients, which includes renal complications. To test whether mutations in Notch1 could increase the severity of renal complications in ALGS, we inactivated conditional Notch1 and Notch2 alleles in mice using a Six2-GFP::Cre. This BAC transgene is expressed mosaically in renal epithelial progenitors but uniformly in cells exiting the progenitor pool to undergo mesenchymal-to-epithelial transition. Although delaying Notch2 inactivation had a marginal effect on nephron numbers, it created a sensitized background in which the inactivation of Notch1 severely compromised nephron formation, function, and survival. These and additional observations indicate that Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J-dependent manner. A significant implication is that elevating Notch1 activity could improve renal functions in ALGS2 patients. As proof of principle, we determined that conditional inactivation of Mint, an inhibitor of Notch-RBP-J interaction, resulted in a moderate rescue of Notch2 null kidneys, implying that temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients.     

TGF-Mediated Dynamics in a System of Many Coupled Nephrons

This paper presents a mathematical model of a system of many coupled nephrons branching from a common cortical radial artery, and accompanying analysis of that system. This modeling effort is a first step in understanding how coupling magnifies the tendency of nephrons to oscillate owing to tubuloglomerular feedback. Central to the present work is the single nephron integral model (as in Pitman et al., The IMA Volumes in Mathematics and Its Applications, vol. 129, pp. 345–364, 2002 and in Zaritski, Ph.D. Dissertation, 1999) which is a simplification of the single nephron PDE model of Layton et al. (Am. J. Physiol. 261, F904–F919, 1991). A second principal idea used in the present model is a coupling of model nephrons, generalizing the work of Pitman et al. (Bull. Math. Biol. 66, 1463–1492, 2004) who proposed a model of two coupled nephrons. In this study, we couple nephrons through a nearest neighbor interaction. Speaking generally, our results suggest that a series of similar nephrons coupled to their nearest neighbors are more prone to be found in an oscillatory mode, relative to a single nephron with the same properties. More specifically, we show analytically that, for N coupled identical nephrons, the region supporting oscillatory solutions in the time delay–gain parameter plane increases with N. Numerical simulations suggest that, if N nephrons have gains and time delays that do not differ by much, the system is, again, more prone to oscillate, relative to a single nephron, and the oscillations tend to be approximately synchronous and in-phase. We examine the effect of parameters on bifurcation. We also examine alternative models of coupling; this analysis allows us to conclude that the increased propensity of coupled nephrons to oscillate is a robust finding, true for several models of nephron interaction.     

Intrarenal Renin Angiotensin System Revisited: ROLE OF MEGALIN-DEPENDENT ENDOCYTOSIS ALONG THE PROXIMAL NEPHRON

The existence of a local renin angiotensin system (RAS) of the kidney has been established. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and high concentrations of luminal angiotensin II have been found in the proximal tubule. Although functional data have documented the relevance of a local RAS, the dualism between biosynthesis and endocytotic uptake of its components and their cellular processing has been incompletely understood. To resolve this, we have selectively analyzed their distribution, endocytosis, transcytosis, and biosynthesis in the proximal tubule. The presence of immunoreactive AGT, restricted to the early proximal tubule, was due to its retrieval from the ultrafiltrate and storage in endosomal and lysosomal compartments. Cellular uptake was demonstrated by autoradiography of radiolabeled AGT and depended on intact endocytosis. AGT was identified as a ligand of the multiple ligand-binding repeats of megalin. AGT biosynthesis was restricted to the proximal straight tubule, revealing substantial AGT mRNA expression. Transgenic AGT overexpression under the control of an endogenous promoter was also restricted to the late proximal tubule. Proximal handling of renin largely followed the patterns of AGT, whereas its local biosynthesis was not significant. Transcytotic transport of AGT in a proximal cell line revealed a 5% recovery rate after 1 h. ACE was expressed along late proximal brush-border membrane, whereas ACE2 was present along the entire segment. Surface expression of ACE and ACE2 differed as a function of endocytosis. Our data on the localization and cellular processing of RAS components provide new aspects of the functional concept of a “self-contained” renal RAS.     

Cells and intercellular contacts in glomeruli and tubules of the frog kidney

Summary By the use of thin sections and freeze-fracture replicas the glomerular and tubular structures of the kidney of the frog (Rana esculenta) were studied with special reference to intercellular junctions.In the glomerulus the filtration barrier is of very variable thickness, and frequent tight and gap junctional contacts occur between podocyte processes.Although structurally less elaborate, the proximal tubule resembles its mammalian counterpart. In the initial part the tight junctions are relatively shallow but become very broad in the mid and distal portions of the proximal tubule. The proximal tubular cells are extensively linked by gap junctions. In some animals the shapes of the cells in the proximal and distal portions of the proximal tubule were markedly different.The distal tubule consists of two segments which differ mainly in the pattern of interdigitations and the structure of the zonulae occludentes. Similarities with the tight junctional morphology of the mammalian distal tubule are striking. In the first part of the distal tubule (diluting segment) a narrow band of parallel tight junctions is found closely resembling that found in the mammalian straight distal tubule; in the more distal part of the distal tubule, however, a broad band of anastomosing tight junctional strands exists, like the zonula occludens of the mammalian convoluted distal tubule.The connecting tubule displays cellular dimorphism: its wall contains a mixture of light and dark (flask) cells. The luminal and basolateral membranes of the flask cells are covered with numerous rod-shaped particles. The tight junctions of the connecting tubule are broad and increase in depth and number of strands along its length; they are typical of a very tight epithelium.In spite of several dissimilarities with phylogenetically younger kidneys our findings suggest that many structural principles of the mammalian kidney are also represented in the kidneys of amphibians. The structural-functional relationships are discussed.     

肾嗜酸细胞腺瘤的诊疗分析（附47 例报告）

目的:分析肾嗜酸细胞腺瘤的临床特征,指导并提升诊疗水平。方法:回顾性分析47例肾嗜酸细胞腺瘤的临床资料,包括临床特点、影像表现、病理特征、治疗方法及预后等方面。结果:47例患者中43例因查体偶然发现,仅4例表现为患侧腰痛症状。术前影像诊断中1例考虑嗜酸细胞腺瘤,1例考虑腺瘤,2例CT与MRI报告不一致(CT与MRI各有1例诊断良性,具体类型不确定),其余43例均诊断为肾细胞癌(1例囊性肾癌)。27例行肾癌根治性切除术,16例行肾部分切除术,4例行微波或射频消融术。所有患者术后病理均诊断为肾嗜酸细胞腺瘤,随访4～179月,均无转移或复发。结论:肾嗜酸细胞腺瘤作为一种与肾细胞癌难相鉴别的良性肿瘤,因缺乏特异性表现,极易误诊为肾细胞癌,因此对肾肿瘤患者应尽可能选择保肾治疗方案。     

Roles and regulation of bone morphogenetic protein-7 in kidney development and diseases

The gene encoding bone morphogenetic protein-7(BMP7) is expressed in the developing kidney in embryos and also in the mature organ in adults. During kidney development, expression of BMP7 is essential to determine the final number of nephrons in and proper size of the organ. The secreted BMP7 acts on the nephron progenitor cells to exert its dual functions: To maintain and expand the progenitor population and to provide them with competence to respond to differentiation cues, each relying on distinct signaling pathways. Intriguingly, in the adult organ, BMP7 has been implicated in protection against and regeneration from injury. Exogenous administration of recombinant BMP7 to animal models of kidney diseases has shown promising effects in counteracting inflammation, apoptosis and fibrosis evoked upon injury. Although the expression pattern of BMP7 has been well described, the mechanisms by which it is regulated have remained elusive and the processes by which the secretion sites of BMP7 impinge upon its functions in kidney development and diseases have not yet been assessed. Understanding the regulatory mechanisms will pave the way towards gaining better insight into the roles of BMP7, and to achieving desired control of the gene expression as a therapeutic strategy for kidney diseases.