Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth

Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.

The mutual patterning between the developing nephron and its covering tissues—valid reasons to rethink the search for traces left by impaired nephrogenesis

Background The impairment of nephrogenesis can cause the termination of nephron formation in preterm and low birth weight babies. This leads to oligonephropathy with severe health consequences in later life. Although many clinical parameters are known, surprisingly little information is available regarding the initial damage on the developing nephron. Equally astounding, the first morphological data regarding the specifics of nephron formation in the nephrogenic zone of the fetal human kidney during late gestation has only been published within the past few years. In this context, it was observed that each stage of nephron anlage is surrounded by a specific set of tissues. Although highly relevant for the normal progress of nephron formation, the mutual patterning has not been systematically described. Results To contribute, the different stages of nephron anlage in the nephrogenic zone of the fetal human kidney during late gestation were screened by the optical microscope and documented by images. Following this, magnifications (28 × 18 cm) were produced to trace the contours of the developing nephron and its covering tissues. The resulting sketches, almost true to scale, were scanned, edited, and processed by a design program. As a base, first the individual position, size, and shape of the nephrogenic niche, pretubular aggregate, renal vesicles, comma- and S-shaped bodies are presented. Secondly, their structural relations to the renal capsule, collecting duct ampulla, perforating radiate artery, and expanding interstitium are shown. Third of all, the focus is on less considered configurations, such as site-specific approximation, local distancing, punctual adhesion, integration, separation, delamination, formation of congruent and divergent surfaces, and folding and opening of interstitial clefts. Conclusions The present contribution illuminates the mutual patterning between the developing nephron and its covering tissues. It is indispensable to know about the microanatomical relations, in order to identify whether the noxae impairing nephrogenesis targets only the developing nephron or also its covering tissues as interacting and controlling instances.

Calreticulin Deficiency Disturbs Ribosome Biogenesis and Results in Retardation in Embryonic Kidney Development

Nephrogenesis is driven by complex signaling pathways that control cell growth and differentiation. The endoplasmic reticulum chaperone calreticulin (Calr) is well known for its function in calcium storage and in the folding of glycoproteins. Its role in kidney development is still not understood. We provide evidence for a pivotal role of Calr in nephrogenesis in this investigation. We show that Calr deficiency results in the disrupted formation of an intact nephrogenic zone and in retardation of nephrogenesis, as evidenced by the disturbance in the formation of comma-shaped and s-shaped bodies. Using proteomics and transcriptomics approaches, we demonstrated that in addition to an alteration in Wnt-signaling key proteins, embryonic kidneys from Calr−/− showed an overall impairment in expression of ribosomal proteins which reveals disturbances in protein synthesis and nephrogenesis. CRISPR/cas9 mediated knockout confirmed that Calr deficiency is associated with a deficiency of several ribosomal proteins and key proteins in ribosome biogenesis. Our data highlights a direct link between Calr expression and the ribosome biogenesis.

Histogenesis of human fetal kidney from 14 weeks to 36 weeks: a study

Background: The knowledge of fetal human Kidney morphology and developmental anatomy is very important for prenatal diagnosis of disorders such as Wilm’s tumor, hydronephroses and congenital malformation etc.Methods: The study was carried out on 40 kidneys procured from 20 spontaneously aborted fetuses (11males and 9 females) ranging from 14wks-36wks of gestation, after confirming their age through CRL they were grouped and then processed to form slides and stained with haemtoxylin and eosin and seen under light microscope.Results: All kidneys were lobulated at early gestational age and became fused by 36 wks. Corticomedullary junction and preformed collecting tubules were seen clearly by 18wks. Well differentiated PCT and DCT were formed by 19-23 wks. Well-formed pyramids by 28 wks and medullary rays by 29 weeks were clearly distinguished. Loop of Henle developed and distinguished by 28 wks. Increased vascularity was seen by 32-36 wks. Nephrogenic zone and undifferentiated mesenchyme decreased and matured glomeruli increased by 36 wks.Conclusions: The present study gave emphasis to the development of each component in medulla and cortex of kidney.

Molecular characterization of nephron progenitors and their early epithelial derivative structures in the nephrogenic zone of the canine fetal kidney

Nephron progenitors (NPs) and nephrogenesis have been extensively studied in mice and humans and have provided insights into the mechanisms of renal development, disease and possibility of NP-based therapies. However, molecular features of NPs and their derivatives in the canine fetal kidney (CFK) remain unknown. This study was focused to characterize the expression of potential markers of canine NPs and their derivatives by immuno-fluorescence and western blot analysis. Transcription factors (TFs) SIX1 and SIX2, well-characterized human NP markers, were expressed in NPs surrounding the ureteric bud in the CFK. Canine NPs also expressed ITGA8 and NCAM1, surface markers previously used to isolate NPs from the mouse and human fetal kidneys. TF, PAX2 was detected in the ureteric bud, NPs and their derivative structures such as renal vesicle and S-shaped body. This study highlights the similarities in dog, mouse and human renal development and characterizes markers to identify canine NPs and their derivatives. These results will facilitate the isolation of canine NPs and their functional characterization to develop NP-based therapies for canine renal diseases.

In Search of Imprints Left by the Impairment of Nephrogenesis

Clinical aspects dealing with the impairment of nephrogenesis in preterm and low birth weight babies were intensely researched. In this context it was shown that quite different noxae can harm nephron formation, and that the morphological damage in the fetal kidney is rather complex. Some pathological findings show that the impairment leads to changes in developing glomeruli that are restricted to the maturation zone of the outer cortex in the fetal human kidney. Other data show also imprints on the stages of nephron anlage including the niche, the pretubular aggregate, the renal vesicle, and comma- and S-shaped bodies located in the overlying nephrogenic zone of the rodent and human kidneys. During our investigations it was noticed that the stages of nephron anlage in the fetal human kidney during the phase of late gestation have not been described in detail. To contribute, these stages were recorded along with corresponding images. The initial nephron formation in the rodent kidney served as a reference. Finally, the known imprints left by the impairment in both specimens were listed and discussed. In sum, the relatively paucity of data on nephron formation in the fetal human kidney during the late phase of gestation is a call to start with intense research so that concepts for a therapeutic prolongation of nephrogenesis can be designed.

Developmental changes in human fetal kidney

Aims and objectives : It is necessary to know the normal developmental Anatomy of the kidney to understand certain prenatal disorders like polysystic kidney, hydronephrosis and Wilm's tumour. A detailed description of histological development of kidney is scarce. Therefore the present study is an attempt to further the anatomical knowledge in histogenesis of kidney. Materials & Method : The study was carried out in the department of Anatomy, Mount Zion Medical College, Adoor, Kerala. 30 dead born fetuses (gestational age range from 11 weeks to 3 6 weeks) were utilized for the study. Tissue specimen from the kidneys were stained with Hematoxylin and Eosin and examined under light microscope. Results: Nephrogenic zone was identified up to 34 wks of gestation. Cortex was clearly distinguished from medulla at 14 th wk of fertilization. Different shapes [S & C] of glomeruli were identified in the second trimester. At 24 th wk, proximal convoluted tubule [PCT], distal convoluted tubule [DCT], collecting duct and thin and thick segment of loop of Henle were identified clearly. Conclusion: The pathological conditions of the kidney can be diagnosed at the earliest by understanding the normal histological development of the kidney at various stages. This study would be helpful for understanding the normal histological development of kidney.