Temporal Expression and Cellular Localization of PAPPA2 in the Developing Kidney of Rat

PAPPA2 is a metalloproteinase which cleaves insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5, and its role in pregnancy and postnatal growth is primarily studied. Using exclusion mapping, we reported a subcongenic (26-P) rat where a 0.71-Mbp region containing the pregnancy-associated plasma protein a2 ( Pappa2) allele of salt-insensitive Brown Norway (BN) was introgressed into Dahl saltsensitive (SS) genetic background, resulting in the reduction of salt sensitivity. Pappa2 was differentially expressed in the adult kidney of 26-P and SS rats. Here, the expression and cellular localization of Pappa2 in embryonic and postnatal kidneys of 26-P and SS rats were examined. Pappa2 mRNA expression was 5-fold higher in the embryonic kidney (day 20.5) of the 26-P rat compared with the SS rat. Pappa2 mRNA expression progressively increased with the development of kidney, reaching a peak at postnatal day 5 before trending downward in subsequent stages of development in both strains. At all tested time points, Pappa2 remained higher in the 26-P compared with the SS rat kidney. Immunohistochemistry studies localized PAPPA2 in the ureteric bud (UB) and distal part of S-shaped body. PAPPA2 was colocalized with IGFBP-5 in the UB and Na+/K+/2Cl− cotransporter–stained tubules, respectively. Future studies are needed to determine the role of Pappa2 in kidney development and mechanistic pathways involved in this process.

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Abstract 094: Pappa2 is Important for Determining the Nephron Number

Hypertension ◽

10.1161/hyp.68.suppl_1.094 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Vikash Kumar ◽

Chun Yang ◽

Aron M Geurts ◽

Mingyu Liang ◽

Allen W Cowley

Keyword(s):

Mrna Expression ◽

Kidney Development ◽

Brown Norway ◽

Ureteric Bud ◽

Induced Hypertension ◽

Allele Variant ◽

Rat Strain ◽

Nephron Development ◽

And Function ◽

Igfbp 3

Pappa2 is a metalloproteinase which specifically cleaves IGFBP-3 and IGFBP-5 and in turn releases IGF-1. Recently, we have shown that a subcongenic Dahl salt-sensitive (SS) rat strain containing a 0.71 Mbp of chromosome 13 which includes Pappa2 gene from salt-insensitive Brown Norway (26-P strain) is protected significantly (24 mmHg) from salt-induced hypertension (Cowley et al., 2016). Although it is recognized that Pappa2 modulates development of bone size, cranial cartilage and angiogenesis, its role in kidney development and function is unknown. The present study determined the contribution of Pappa2 to nephron development by comparing SS and 26-P rat strains. It was found that Pappa2 mRNA expression was 5-fold higher in embryonic kidney (day 20.5) of the salt-resistant 26-P rats compared with age-matched SS rats. Pappa2 mRNA expression significantly increased with age of kidney reaching a maximum at postnatal day 5 in both strains. Pappa2 mRNA expression at postnatal day 15 was found to be 9-fold higher in the kidney of 26-P compared with SS strain. Immunohistochemistry studies revealed that Pappa2 co-localized with IGFBP-5 in the ureteric bud indicating that Pappa2 could be important for ureteric branching and nephron endowment. Glomerulus/mm 2 was therefore determined by counting total number of glomeruli in kidney sections from pups starting from P0 to P20. The salt-resistant 26-P congenic strain exhibited significantly greater nephron density 9.03 and 7.07 glo/mm 2 compared to 6.89 and 4.85 glo/mm 2 in SS rat at day P15 and P20, respectively. It appears that the Brown Norway pappa2 allele variant prevents the reduced nephron numbers observed in SS rats and thereby protects these congenic rats from salt-induced hypertension.

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State of the Art on Kidney Development: How Nephron Endowment at Birth Can Shape Our Susceptibility to Renal Dysfunction Later in Life

American Journal of Perinatology ◽

10.1055/s-0039-1691798 ◽

2019 ◽

Vol 36 (S 02) ◽

pp. S33-S36 ◽

Cited By ~ 2

Author(s):

Vassilios Fanos ◽

Clara Gerosa ◽

Cristina Loddo ◽

Gavino Faa

Keyword(s):

Birth Weight ◽

Fetal Programming ◽

Low Birthweight ◽

Kidney Development ◽

State Of The Art ◽

Kidney Diseases ◽

Nephron Endowment ◽

Adult Kidney ◽

Maternal Status

AbstractIn the present article, we discuss the following topics: (1) the fetal programming of adult kidney diseases and (2) the role of neonatologists in the regenerative renal medicine, based on the activation of resident renal SC. Here, we report the most important steps of our collaboration between neonatologists, nephrologists, and pathologists. Nephrologists should be more interested in clinical data regarding the first month of life in the womb of their adult patients, being particularly focused on birth weight and on the weeks of gestation at birth, without forgetting data regarding maternal status during gestation and neonatal asphyxia. Neonatologists should be aware that any preterm or low birthweight infant should be considered as a subject with fewer glomeruli, probably predicted to develop renal disease later in life.

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Developmental expression of aquaporin 1 in the rat renal vasculature

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.4.f498 ◽

1999 ◽

Vol 276 (4) ◽

pp. F498-F509 ◽

Cited By ~ 10

Author(s):

Jin Kim ◽

Wan-Young Kim ◽

Ki-Hwan Han ◽

Mark A. Knepper ◽

Søren Nielsen ◽

...

Keyword(s):

Kidney Development ◽

Rat Kidney ◽

Water Channel ◽

Developmental Expression ◽

Renal Tubules ◽

Renal Vasculature ◽

Aquaporin 1 ◽

Vasa Recta ◽

Adult Kidney ◽

Developing Rat

Aquaporin 1 (AQP-1) is a water channel protein that is constitutively expressed in renal proximal tubule and descending thin limb cells as well as in endothelial cells of the descending vasa recta. Studies in the developing rat kidney have demonstrated that AQP-1 is expressed in renal tubules before birth. However, nothing is known about the expression of AQP-1 in the renal vasculature during kidney development. The purpose of this study was to establish the distribution of AQP-1 in the renal vasculature of the developing rat kidney and follow the differentiation of the vascular system during kidney development. Kidneys from 16-, 17-, 18-, and 20-day-old fetuses and 1-, 4-, 7-, 14-, 21-, and 28-day-old pups were preserved and processed for immunohistochemical studies using a preembedding immunoperoxidase procedure. AQP-1 immunoreactivity was detected using affinity-purified rabbit polyclonal antibodies to AQP-1. AQP-1 was expressed throughout the arterial portion of the renal vasculature of the fetal and neonatal kidney from gestational age 17 days to 1 wk after birth. AQP-1 immunoreactivity gradually disappeared from the renal vasculature between 1 and 2 wk of age and remained only in the descending vasa recta. In contrast, AQP-1 immunoreactivity was not observed in lymphatic vessels until 3 wk of age and persisted in the adult kidney. AQP-1 was also expressed in a population of interstitial cells in the terminal part of the renal papilla at 3 wk of age as well as in the adult kidney. The transient expression of AQP-1 in the arterial portion of the renal vasculature in the developing rat kidney suggests that AQP-1 is important for fluid equilibrium and/or drainage in the developing kidney or, alternatively, plays a role in the regulation of growth and/or branching of the vascular tree during kidney development.

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Maturation of TonEBP expression in developing rat kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00047.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. F878-F885 ◽

Cited By ~ 29

Author(s):

Ki-Hwan Han ◽

Seung Kyoon Woo ◽

Wan-Young Kim ◽

Soo-Hyun Park ◽

Jung-Ho Cha ◽

...

Keyword(s):

Target Genes ◽

Kidney Development ◽

Rat Kidney ◽

Renal Medulla ◽

Organic Osmolytes ◽

Vasa Recta ◽

Enhancer Binding Protein ◽

Genes Encoding ◽

Urinary Concentrating Ability

Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator of the Rel family. In the renal medulla, TonEBP stimulates genes encoding proteins involved in cellular accumulation of organic osmolytes, the vasopressin-regulated urea transporters (UT-A), and heat shock protein 70. To understand the role of TonEBP in the development of urinary concentrating ability, TonEBP expression during rat kidney development was investigated. In embryonic kidneys, TonEBP immunoreactivity was detected 16 days postcoitus in the cytoplasm of the endothelial cells surrounding the medullary collecting ducts (MCD). By 20 days, TonEBP was detected in most tubular profiles in the medulla, including the loop of Henle and MCD, and interstitial cells. The intensity of TonEBP immunoreactivity was much higher in the vasa recta than the tubules. In addition, immunoreactivity was localized predominantly to the cytoplasm. On postnatal day 1, two major changes were observed. TonEBP immunoreactivity shifted to the nucleus, and the intensity of TonEBP immunoreactivity of the tubules increased dramatically. These changes were associated with an increase in TonEBP and sodium- myo-inositol cotransporter mRNA abundance. Thereafter, TonEBP expression in tubular profiles increased moderately. The adult pattern of TonEBP expression was established at postnatal day 21 coincident with full maturation of the renal medulla. Thus expression of TonEBP in developing kidneys occurred predominantly in the medulla and preceded expression of its target genes, including UT-A. These data suggest that TonEBP contributes to the development of urine-concentrating ability.

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Expression of AQP family in rat kidneys during development and maturation

AJP Renal Physiology ◽

10.1152/ajprenal.1997.272.2.f198 ◽

1997 ◽

Vol 272 (2) ◽

pp. F198-F204 ◽

Cited By ~ 13

Author(s):

T. Yamamoto ◽

S. Sasaki ◽

K. Fushimi ◽

K. Ishibashi ◽

E. Yaoita ◽

...

Keyword(s):

Mrna Expression ◽

Kidney Development ◽

Collecting Duct ◽

Rat Kidney ◽

Staining Intensity ◽

Ribonuclease Protection Assay ◽

Duct Cells ◽

Apical Side ◽

Basolateral Side ◽

Collecting Duct Cells

The mRNA expression and localization of the aquaporin (AQP) family in rat kidney were examined by ribonuclease protection assay and immunohistochemistry. AQP1, AQP2, AQP3, and AQP4 mRNA were hardly detectable in 16-day gestation fetuses. AQP1 mRNA was explosively expressed at 1 wk, keeping the level throughout life. AQP2 mRNA expression was apparently noticed in 18-day fetuses and was enhanced gradually with age to reach a plateau at 4 wk. AQP3 and AQP4 mRNA expression was significantly found at birth but was not changed remarkably thereafter. AQP2 protein appeared first at the apical side of collecting duct cells in 18-day fetuses. The staining intensity at the site increased with age, and basolateral staining was added in adult rats. AQP3 was distinctly demonstrated at the basolateral side of collecting duct cells after birth, and the staining intensity was almost stable throughout life. The progressive induction of AQP2 expression in the first 4 wk after birth is presumed to contribute to the maturation of urinary concentrating capacity during the kidney development.

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Troy/TNFRSF19 marks epithelial progenitor cells during mouse kidney development that continue to contribute to turnover in adult kidney

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714145115 ◽

2017 ◽

Vol 114 (52) ◽

pp. E11190-E11198 ◽

Cited By ~ 6

Author(s):

Frans Schutgens ◽

Maarten B. Rookmaaker ◽

Francis Blokzijl ◽

Ruben van Boxtel ◽

Robert Vries ◽

...

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Kidney Development ◽

Collecting Duct ◽

Adult Kidney ◽

Cell Property ◽

Developing Kidney ◽

Nephron Progenitor ◽

Epithelial Progenitor Cells

During kidney development, progressively committed progenitor cells give rise to the distinct segments of the nephron, the functional unit of the kidney. Similar segment-committed progenitor cells are thought to be involved in the homeostasis of adult kidney. However, markers for most segment-committed progenitor cells remain to be identified. Here, we evaluate Troy/TNFRSF19 as a segment-committed nephron progenitor cell marker. Troy is expressed in the ureteric bud during embryonic development. During postnatal nephrogenesis, Troy+ cells are present in the cortex and papilla and display an immature tubular phenotype. Tracing of Troy+ cells during nephrogenesis demonstrates that Troy+ cells clonally give rise to tubular structures that persist for up to 2 y after induction. Troy+ cells have a 40-fold higher capacity than Troy− cells to form organoids, which is considered a stem cell property in vitro. In the adult kidney, Troy+ cells are present in the papilla and these cells continue to contribute to collecting duct formation during homeostasis. The number of Troy-derived cells increases after folic acid-induced injury. Our data show that Troy marks a renal stem/progenitor cell population in the developing kidney that in adult kidney contributes to homeostasis, predominantly of the collecting duct, and regeneration.

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Expression of epidermal growth factor in the developing rat kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00058.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. F227-F235 ◽

Cited By ~ 14

Author(s):

Ju-Young Jung ◽

Ji-Hyun Song ◽

Can Li ◽

Chul-Woo Yang ◽

Tae-Cheon Kang ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Kidney Development ◽

Rat Kidney ◽

Distal Tubule ◽

Distal Convoluted Tubule ◽

Thick Ascending Limb ◽

Epidermal Growth ◽

Developing Kidney ◽

Developing Rat

Epidermal growth factor (EGF) is important in mammalian renal development. In our study, we investigated the detailed distribution and the time of the first appearance of EGF in developing rat kidney. Kidneys from embryonic 18 ( E18)- and 20-day-old ( E20) fetuses, postnatal 1 ( P1)-, 3 ( P3)-, 7 ( P7)-, 14 ( P14)-, and 21-day-old ( P21) pups, and adults were processed for immunohistochemistry and electronmicroscopy. In adult rat kidney, EGF immunoreactivity was found in distal tubule including the thick ascending limb (TAL) and portion 1 of distal convoluted tubule (DCT1), whereas no EGF immunoreactivity was seen in portion 2 of distal convoluted tubule (DCT2) and connecting tubule. In developing kidney, EGF-positive cells first appeared at P3 and were localized in the middle portion of the differentiating TAL of the corticomedullary junction. By P7, the abundance of EGF expression had dramatically increased in the medullary TAL. Between P14 and P21, EGF immunoreactivity was found in the TAL and the DCT for the first time. However, EGF-positive and EGF-negative cells were in the TAL in developing rat kidney. EGF-positive cells did not differ from negative cells in the expression of sodium transport proteins or in the proliferation rate at P3 and P7. In the TAL, smooth-surfaced cells had strong EGF immunoreactivity, but no EGF immunoreactivity was seen in the rough-surfaced cells with well-developed microvilli. Our results suggest that the expression of EGF in developing kidney plays an important role in the regulation of growth and differentiation of the loop of Henle during kidney development and that this may act in the paracrine mode.

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