Abstract 094: Pappa2 is Important for Determining the Nephron Number

Hypertension ◽  
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.

Sulphated proteoglycan is required for collecting duct growth and branching but not nephron formation during kidney development

Development ◽  
1995 ◽  
Vol 121 (5) ◽  
pp. 1507-1517 ◽  
Author(s):  
J. Davies ◽  
M. Lyon ◽  
J. Gallagher ◽  
D. Garrod
Keyword(s):  
Kidney Development ◽  
Collecting Duct ◽  
Sodium Chlorate ◽  
Ureteric Bud ◽  
Nephron Differentiation ◽  
Bud Growth ◽  
Nephron Development ◽  
Sulphated Glycosaminoglycans ◽  
Sulphated Proteoglycan ◽  
Hepatocyte Growth

Kidney epithelia have separate origins; collecting ducts develop by ureteric bud growth and arborisation, nephrons by induced mesenchyme-epithelium transition. Both express sulphated glycosaminoglycans (GAGs) which are strikingly upregulated during nephron differentiation. However, sodium chlorate, an inhibitor of GAG sulphation, and the GAG-degrading enzymes heparitinase plus chondroitinase, did not prevent nephron development. In contrast, ureteric bud growth and branching were reversibly inhibited by the above reagents, the inhibition correlating quantitatively with sulphated GAG deprivation caused by a range of chlorate concentrations. Growth and branching could be independently restored during GAG deprivation by hepatocyte growth factor and phorbol-12-myristate acetate (PMA) respectively. Together these signalling effectors stimulated both branch initiation and growth. Thus growth and morphogenesis of ureteric bud involve distinct signalling pathways both regulated by GAGs.

scholarly journals Skeletal muscle IGF-binding protein-3 and -5 expressions are age, muscle, and load dependent

2003 ◽  
Vol 284 (2) ◽  
pp. E340-E350 ◽  
Author(s):  
Espen E. Spangenburg ◽  
Tsghe Abraha ◽  
Tom E. Childs ◽  
J. Scott Pattison ◽  
Frank W. Booth
Keyword(s):  
Mrna Expression ◽  
Soleus Muscle ◽  
Gastrocnemius Muscle ◽  
Muscle Size ◽  
Brown Norway ◽  
Type I ◽  
Fischer 344 ◽  
Muscle Aging ◽  
Muscle Groups ◽  
Igfbp 3

The purpose of the current study was to examine IGFBP-3, -4, and -5 mRNA and protein expression levels as a function of muscle type, age, and regrowth from an immobilization-induced atrophy in Fischer 344 × Brown Norway rats. IGFBP-3 mRNA expression in the 4-mo-old animals was significantly higher in the red and white portions of the gastrocnemius muscle compared with the soleus muscle. However, there were no significant differences in IGFBP-3 mRNA expression among any of the muscle groups in the 30-mo-old animals. There were no significant differences in IGFBP-5 mRNA expression in any of the muscle groups, whereas in the 30-mo-old animals there was significantly less IGFBP-5 mRNA expression in the white gastrocnemius compared with the red gastrocnemius muscles. Although IGFBP-3 and -5 proteins were detected in the type I soleus muscle with Western blot analyses, no detection was observed in the type II red and white portions of the gastrocnemius muscle. Aging from adult (18 mo) to old animals (30 mo) was associated with decreases in IGFBP-3 mRNA and protein and IGFBP-5 protein only in the soleus muscle. After 10 days of recovery from 10 days of hindlimb immobilization, IGFBP-3 mRNA and protein increased in soleus muscles from young (4-mo) rats; however, only IGFBP-3 protein increased in the old (30-mo) rats. Whereas there were no changes in IGFBP-5 mRNA expression during recovery, IGFBP-5 protein in the 10-day-recovery soleus muscle did increase in the young, but not in the old, rats. Because one of the functions of IGFBPs is to modulate IGF-I action on muscle size and phenotype, it is hypothesized that IGFBP-3 and -5 proteins may have potential modulatory roles in type I fiber-dominated muscles, aging, and regrowth from atrophy.

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

2020 ◽  
Vol 68 (3) ◽  
pp. 209-222
Author(s):  
Vikash Kumar ◽  
Chun Yang ◽  
Allen W. Cowley
Keyword(s):  
Mrna Expression ◽  
Cellular Localization ◽  
Kidney Development ◽  
Rat Kidney ◽  
Postnatal Growth ◽  
Brown Norway ◽  
Adult Kidney ◽  
Developing Kidney ◽  
P 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.

Long-term diet-induced hypertension in rats is associated with reduced expression and function of small artery SKCa, IKCa, and Kir2.1 channels

2018 ◽  
Vol 132 (4) ◽  
pp. 461-474 ◽  
Author(s):  
Anna K.J. Gradel ◽  
Max Salomonsson ◽  
Charlotte M. Sørensen ◽  
Niels-Henrik Holstein-Rathlou ◽  
Lars Jørn Jensen
Keyword(s):  
Blood Pressure ◽  
Mrna Expression ◽  
Mesenteric Arteries ◽  
K Channel ◽  
High Fat ◽  
K Channels ◽  
High Fructose ◽  
Induced Hypertension ◽  
And Function

Abdominal obesity and/or a high intake of fructose may cause hypertension. K+ channels, Na/K-ATPase, and voltage-gated Ca2+ channels are crucial determinants of resistance artery tone and thus the control of blood pressure. Limited information is available on the role of K+ transporters in long-term diet-induced hypertension in rats. We hypothesized that a 28-week diet rich in fat, fructose, or both, will lead to changes in K+ transporter expression and function, which is associated with increased blood pressure and decreased arterial function. Male Sprague–Dawley (SD) rats received a diet containing normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat/Fruc) for 28 weeks from the age of 4 weeks. Measurements included body weight (BW), systolic blood pressure (SBP), mRNA expression of vascular K+ transporters, and vessel myography in small mesenteric arteries (SMAs). BW was increased in the High Fat and High Fat/Fruc groups, and SBP was increased in the High Fat/Fruc group. mRNA expression of small conductance calcium-activated K+ channel (SKCa), intermediate conductance calcium-activated K+ (IKCa), and Kir2.1 inward rectifier K+ channels were reduced in the High Fat/Fruc group. Reduced endothelium-derived hyperpolarization (EDH)-type relaxation to acetylcholine (ACh) was seen in the High Fat and High Fat/Fruc groups. Ba2+-sensitive dilatation to extracellular K+ was impaired in all the experimental diet groups. In conclusion, reduced expression and function of SKCa, IKCa, and Kir2.1 channels are associated with elevated blood pressure in rats fed a long-term High Fat/Fruc. Rats fed a 28-week High Fat/Fruc provide a relevant model of diet-induced hypertension.

scholarly journals Pappa2 is linked to salt-sensitive hypertension in Dahl S rats

2016 ◽  
Vol 48 (1) ◽  
pp. 62-72 ◽  
Author(s):  
Allen W. Cowley ◽  
Chun Yang ◽  
Vikash Kumar ◽  
Jozef Lazar ◽  
Howard Jacob ◽  
...  
Keyword(s):  
Renal Cortex ◽  
Brown Norway ◽  
Variant Form ◽  
Renal Tubules ◽  
Protein Coding ◽  
Salt Diet ◽  
Induced Hypertension ◽  
Rat Strain ◽  
Apical Membranes ◽  
Salt Sensitive Hypertension

A 1.37 Mbp region of chromosome 13 previously identified by exclusion mapping was consistently associated with a reduction of salt-induced hypertension in the Dahl salt-sensitive (SS) rat. This region contained five genes that were introgressed from the salt-insensitive Brown Norway (BN) rat. The goal of the present study was to further narrow that region to identify the gene(s) most likely to protect from salt-induced hypertension. The studies yielded a subcongenic SS rat strain containing a 0.71 Mbp insert from BN (26-P strain) in which salt-induced hypertension was reduced by 24 mmHg. The region contained two protein-coding genes ( Astn1 and Pappa2) and a microRNA ( miR-488). Pappa2 mRNA in the renal cortex of the protected 26-P was 6- to 10-fold greater than in SS fed a 0.4% NaCl diet but was reduced to levels observed in SS when fed 8.0% NaCl diet for 7 days. Compared with brain nuclei (NTS, RVLM, CVLM) and the adrenal gland, Pappa2 in the renal cortex was the only gene found to be differentially expressed between SS and 26-P and that responded to changes of salt diet. Immunohistochemistry studies found Pappa2 localized in the cytosol of the epithelial cells of the cortical thick ascending limbs. In more distal segments of the renal tubules, it was observed within tubular lumens and most notably bound to the apical membranes of the intercalated cells of collecting ducts. We conclude that we have identified a variant form of Pappa2 that can protect against salt-induced hypertension in the Dahl S rat.

scholarly journals A Secreted BMP Antagonist, Cer1, Fine Tunes the Spatial Organization of the Ureteric Bud Tree during Mouse Kidney Development

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e27676 ◽  
Author(s):  
Lijun Chi ◽  
Ulla Saarela ◽  
Antti Railo ◽  
Renata Prunskaite-Hyyryläinen ◽  
Ilya Skovorodkin ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Kidney Development ◽  
Mouse Kidney ◽  
Ureteric Bud ◽  
Bmp Antagonist

Construction of an lncRNA–mRNA Co-Expression Regulatory Network Mediating Inflammation and Regeneration Following Acute Pancreatitis Injury

2021 ◽  
Author(s):  
Jing Wang ◽  
Tianjie Chen ◽  
Xiaohua Zhang ◽  
Shulei Zhao
Keyword(s):  
Acute Pancreatitis ◽  
Mrna Expression ◽  
Regulatory Network ◽  
Noncoding Rnas ◽  
Pancreatic Injury ◽  
Control Group ◽  
Rna Seq ◽  
Damage Repair ◽  
Injury And Repair ◽  
And Function

Abstract Long noncoding RNAs (lncRNAs) play important roles in the occurrence and development of many diseases and can be used as targets for diagnosis and treatment. However, the expression and function of lncRNAs in the injury and repair of acute pancreatitis (AP) are unclear. To decipher lncRNAs’ regulatory roles in AP, we reanalyzed an RNA-seq dataset of 24 pancreatic tissues, including those of normal control mice (BL), those 7 days after mild AP (D7), and those 14 days after mild AP (D14). The results showed significant differences in lncRNA and mRNA expression of D7/D14 groups compared with the control group. Co-expression analysis showed that differentially expressed (DE) lncRNAs were closely related to immunity- and inflammation-related pathways by trans-regulating mRNA expression. The lncRNA–mRNA network showed that the lncRNAs Dancer, Gmm20488, Terc, Snhg3, and Snhg20 were significantly correlated with AP pathogenesis. WGCNA and cis regulation analysis also showed that AP repair-associated lncRNAs were correlated with extracellular and inflammation-related genes, which affect the repair and regeneration of pancreatic injury after AP. In conclusion, the systemic dysregulation of lncRNAs is strongly involved in remodeling AP’s gene expression regulatory network, and the lncRNA–mRNA expression network could identify targets for AP treatment and damage repair.

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