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Assessment of unilateral ureter obstruction with multi-parametric MRI.
Wang F, Takahashi K, Li H, Zu Z, Li K, Xu J, Harris RC, Takahashi T, Gore JC
(2018) Magn Reson Med 79: 2216-2227
MeSH Terms: Algorithms, Animals, Contrast Media, Diffusion, Disease Models, Animal, Fibrosis, Image Interpretation, Computer-Assisted, Kidney, Kidney Cortex, Magnetic Resonance Imaging, Mice, Mice, Inbred C57BL, Reproducibility of Results, Signal-To-Noise Ratio, Ureter, Ureteral Obstruction
Show Abstract · Added August 17, 2017
PURPOSE - Quantitative multi-parametric MRI (mpMRI) methods may allow the assessment of renal injury and function in a sensitive and objective manner. This study aimed to evaluate an array of MRI methods that exploit endogenous contrasts including relaxation rates, pool size ratio (PSR) derived from quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), nuclear Overhauser enhancement (NOE), and apparent diffusion coefficient (ADC) for their sensitivity and specificity in detecting abnormal features associated with kidney disease in a murine model of unilateral ureter obstruction (UUO).
METHODS - MRI scans were performed in anesthetized C57BL/6N mice 1, 3, or 6 days after UUO at 7T. Paraffin tissue sections were stained with Masson trichrome following MRI.
RESULTS - Compared to contralateral kidneys, the cortices of UUO kidneys showed decreases of relaxation rates R and R , PSR, NOE, and ADC. No significant changes in CEST effects were observed for the cortical region of UUO kidneys. The MRI parametric changes in renal cortex are related to tubular cell death, tubular atrophy, tubular dilation, urine retention, and interstitial fibrosis in the cortex of UUO kidneys.
CONCLUSION - Measurements of multiple MRI parameters provide comprehensive information about the molecular and cellular changes produced by UUO. Magn Reson Med 79:2216-2227, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
© 2017 International Society for Magnetic Resonance in Medicine.
0 Communities
4 Members
0 Resources
16 MeSH Terms
Novel methods for microCT-based analyses of vasculature in the renal cortex reveal a loss of perfusable arterioles and glomeruli in eNOS-/- mice.
Perrien DS, Saleh MA, Takahashi K, Madhur MS, Harrison DG, Harris RC, Takahashi T
(2016) BMC Nephrol 17: 24
MeSH Terms: Animals, Arterioles, Kidney Cortex, Kidney Glomerulus, Male, Mice, Mice, Knockout, Nitric Oxide Synthase Type III, Organ Size, Renal Artery, X-Ray Microtomography
Show Abstract · Added April 13, 2017
BACKGROUND - Two-dimensional measures of vascular architecture provide incomplete information about vascular structure. This study applied a novel rigorous method for 3D microCT-based analysis of total and cortical renal vasculature combined with a novel method to isolate and quantify the number of perfused glomeruli to assess vascular changes in eNOS-/- mice.
METHODS - Two month old male wildtype and eNOS-/- mice were perfused with heparinized saline followed by radiopaque Microfil. The Microfil-perfused vasculature of excised kidneys was imaged by μCT with an isotropic voxel-size of 5.0 μm. For analysis of renal cortical vasculature, a custom algorithm was created to define the cortical volume of interest (VOI) as the entire volume within 600 μm of the renal surface. Vessel thickness in the whole kidney or renal cortex was analyzed by plotting the distribution of vascular volume at each measured thickness and examining differences between the genotypes at individual thicknesses. A second image processing algorithm was created to isolate, identify, and extract contrast perfused glomeruli from the cortical vessels.
RESULTS - Fractional vascular volume (vascular volume/kidney volume; VV/KV) and Vessel Number/mm (V.N) were significantly lower in eNOS-/- mice vs. WT (p < 0.05). eNOS-/- kidneys had significantly fewer perfusable vessels vs. WT in the range of 20-40 μm in thickness. The cortex of eNOS-/- kidneys had significantly lower VV, VV/cortical volume, and V.N, with an increase in the distance between vessels (all p < 0.05). The total volume of vessels in the range of 20-30 μm was significantly lower in the cortex of eNOS-/- mice compared to WT (p < 0.05). Moreover, the total number of perfused glomeruli was significantly decreased in eNOS-/- mice (p < 0.01).
CONCLUSIONS - The methods presented here demonstrate a new method to analyze contrast enhanced μCT images for vascular phenotyping of the murine kidney. These data also demonstrate that kidneys in eNOS-/- mice have severe defects in vascular perfusion/structure in the renal cortex.
2 Communities
3 Members
0 Resources
11 MeSH Terms
Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice.
Zeng F, Miyazawa T, Kloepfer LA, Harris RC
(2014) Kidney Int 86: 538-47
MeSH Terms: Animals, Apoptosis, Blood Urea Nitrogen, Caspase 3, Cell Proliferation, Cyclin D, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, Disease Progression, Epithelial Cells, Fibrosis, Gene Deletion, Kidney Cortex, Kidney Medulla, Mice, Organ Size, Polycystic Kidney Diseases, Receptor, ErbB-4
Show Abstract · Added October 27, 2014
ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Deleting the TGF-β receptor attenuates acute proximal tubule injury.
Gewin L, Vadivelu S, Neelisetty S, Srichai MB, Paueksakon P, Pozzi A, Harris RC, Zent R
(2012) J Am Soc Nephrol 23: 2001-11
MeSH Terms: Acute Kidney Injury, Animals, Apoptosis, Kidney Cortex, Kidney Tubules, Proximal, Male, Mercuric Chloride, Mice, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Smad Proteins, Transforming Growth Factor beta
Show Abstract · Added February 24, 2014
TGF-β is a profibrotic growth factor in CKD, but its role in modulating the kidney's response to AKI is not well understood. The proximal tubule epithelial cell, which is the main cellular target of AKI, expresses high levels of both TGF-β and its receptors. To determine how TGF-β signaling in this tubular segment affects the response to AKI, we selectively deleted the TGF-β type II receptor in the proximal tubules of mice. This deletion attenuated renal impairment and reduced tubular apoptosis in mercuric chloride-induced injury. In vitro, deficiency of the TGF-β type II receptor protected proximal tubule epithelial cells from hydrogen peroxide-induced apoptosis, which was mediated in part by Smad-dependent signaling. Taken together, these results suggest that TGF-β signaling in the proximal tubule has a detrimental effect on the response to AKI as a result of its proapoptotic effects.
1 Communities
4 Members
1 Resources
13 MeSH Terms
Sodium and potassium balance depends on αENaC expression in connecting tubule.
Christensen BM, Perrier R, Wang Q, Zuber AM, Maillard M, Mordasini D, Malsure S, Ronzaud C, Stehle JC, Rossier BC, Hummler E
(2010) J Am Soc Nephrol 21: 1942-51
MeSH Terms: Aldosterone, Animals, Aquaporin 2, Epithelial Sodium Channels, Female, Homeostasis, Kidney Cortex, Kidney Tubules, Kidney Tubules, Collecting, Male, Mice, Mice, Knockout, Mice, Transgenic, Potassium, Sodium, Sodium, Dietary
Show Abstract · Added September 9, 2013
Mutations in α, β, or γ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of αENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking αENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of αENaC in the CCD and weak αENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, αENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.
0 Communities
0 Members
1 Resources
16 MeSH Terms
Rac1 promotes TGF-beta-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism.
Hubchak SC, Sparks EE, Hayashida T, Schnaper HW
(2009) Am J Physiol Renal Physiol 297: F1316-23
MeSH Terms: Actins, Blotting, Northern, Collagen Type I, Fibrosis, Humans, Kidney, Kidney Cortex, Mesangial Cells, Oncogene Protein v-akt, Phosphatidylinositol 3-Kinases, Plasmids, RNA, Transfection, Transforming Growth Factor beta, rac1 GTP-Binding Protein, rho GTP-Binding Proteins, rhoA GTP-Binding Protein
Show Abstract · Added February 11, 2011
Transforming growth factor (TGF)-beta is a central mediator in the progression of glomerulosclerosis, leading to accumulation of aberrant extracellular matrix proteins and inappropriate expression of smooth muscle alpha-actin in the kidney. Previously, we reported that disrupting the cytoskeleton diminished TGF-beta-stimulated type I collagen accumulation in human mesangial cells. As cytoskeletal signaling molecules, including the Rho-family GTPases, have been implicated in fibrogenesis, we sought to determine the respective roles of RhoA and Rac1 in HMC collagen I expression. TGF-beta1 activated both RhoA and Rac1 within 5 min of treatment, and this activation was dependent on the kinase activity of the type I TGF-beta receptor. TGF-beta1-stimulated induction of type I collagen mRNA expression and promoter activity was diminished by inhibiting Rac1 activity and was increased by a constitutively active Rac1 mutant, whereas inhibiting RhoA activity had no such effect. Rac1 activation required phosphatidylinositol-3-kinase (PI3K) activity. Furthermore, the PI3K antagonist, LY294002, reduced TGF-beta1-stimulated COL1A2 promoter activity and Rac1 activation. It also partially blocked active Rac1-stimulated collagen promoter activity, suggesting that PI3K activity contributes to both TGF-beta activation of Rac1 and signal propagation downstream of Rac1. Thus, while both Rac1 and RhoA are rapidly activated in response to TGF-beta1 in human mesangial cells, only Rac1 activation enhances events that contribute to mesangial cell collagen expression, through a positive feedback loop involving PI3K.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Inactivation of Pkd1 in principal cells causes a more severe cystic kidney disease than in intercalated cells.
Raphael KL, Strait KA, Stricklett PK, Miller RL, Nelson RD, Piontek KB, Germino GG, Kohan DE
(2009) Kidney Int 75: 626-33
MeSH Terms: Animals, Kidney Cortex, Kidney Diseases, Cystic, Kidney Medulla, Kidney Tubules, Collecting, Mice, Mice, Knockout, Mice, Transgenic, Phenotype, TRPP Cation Channels
Show Abstract · Added September 9, 2013
Renal cysts in autosomal dominant polycystic kidney disease arise from cells throughout the nephron, but there is an uncertainty as to whether both the intercalated cells (ICs) and principal cells (PCs) within the collecting duct give rise to cysts. To determine this, we crossed mice containing loxP sites within introns 1 and 4 of the Pkd1 gene with transgenic mice expressing Cre recombinase under control of the aquaporin-2 promoter or the B1 subunit of the proton ATPase promoter, thereby generating PC- or IC-specific knockout of Pkd1, respectively. Mice, that had Pkd1 deleted in the PCs, developed progressive cystic kidney disease evident during the first postnatal week and had an average lifespan of 8.2 weeks. There was no change in the cellular cAMP content or membrane aquaporin-2 expression in their kidneys. Cysts were present in the cortex and outer medulla but were absent in the papilla. Mice in which PKd1 was knocked out in the ICs had a very mild cystic phenotype as late as 13 weeks of age, limited to 1-2 cysts and confined to the outer rim of the kidney cortex. These mice lived to at least 1.5 years of age without evidence of early mortality. Our findings suggest that PCs are more important than ICs for cyst formation in polycystic kidney disease.
0 Communities
0 Members
1 Resources
10 MeSH Terms
Renal localization and regulation of 15-hydroxyprostaglandin dehydrogenase.
Yao B, Xu J, Harris RC, Zhang MZ
(2008) Am J Physiol Renal Physiol 294: F433-9
MeSH Terms: Animals, Cell Line, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Epithelial Cells, Epithelium, Gene Expression Regulation, Enzymologic, Hydroxyprostaglandin Dehydrogenases, In Situ Hybridization, Kidney, Kidney Cortex, Kidney Glomerulus, Kidney Medulla, Kidney Tubules, Proximal, Male, Mice, Mice, Inbred Strains, Mice, Knockout, Organic Chemicals, Pyrazoles, Rats, Rats, Sprague-Dawley, Sodium Chloride, Dietary, Sulfonamides, Swine
Show Abstract · Added December 10, 2013
Tissue prostaglandin levels are determined by both biosynthesis and catabolism. The current studies report the expression and localization of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in prostaglandin catabolism in the kidneys. We also investigated potential interactions between 15-PGDH and cyclooxygenase (COX), a key enzyme in prostaglandin biosynthesis. Both 15-PGDH mRNA and protein levels were significantly higher in kidney cortex than in papilla, which is opposite to the expression pattern of COX-2. In situ hybridization indicated that 15-PGDH mRNA was mainly localized to the tubular epithelial cells in kidney cortex and outer medulla but not in the glomerulus or papilla. Dual immunofluorescent staining indicated that 15-PGDH was expressed in the proximal tubule, cortical, and outer medullary thick ascending limb and collecting duct but not in the macula densa or papilla. 15-PGDH levels were significantly lower in a macula densa cell line (MMDD1) than in a proximal tubule cell line. Although a high-salt diet decreased COX-2 expression in macula densa, it increased macula densa 15-PGDH expression in both mouse and rat kidneys. In MMDD1 cells, a COX-2 inhibitor increased 15-PGDH, whereas a COX-1 inhibitor had no effect. Furthermore, intense 15-PGDH immunofluorescent staining was found in both macula densa and glomerulus in COX-2 knockout mice. The intrarenal distribution of 15-PGDH and its interactions with COX-2 suggest that differential regulation of COX-2 and 15-PGDH may play an important role in determining levels of prostaglandins involved in regulation of salt, volume, and blood pressure homeostasis.
2 Communities
2 Members
1 Resources
25 MeSH Terms
Characterization of a putative intrarenal serotonergic system.
Xu J, Yao B, Fan X, Langworthy MM, Zhang MZ, Harris RC
(2007) Am J Physiol Renal Physiol 293: F1468-75
MeSH Terms: Animals, Aromatic-L-Amino-Acid Decarboxylases, Cell Line, Connective Tissue Growth Factor, Immediate-Early Proteins, Immunohistochemistry, In Situ Hybridization, Intercellular Signaling Peptides and Proteins, Kidney Cortex, Kidney Tubules, Proximal, Male, Mice, Mitogen-Activated Protein Kinase Kinases, Phosphorylation, Podocytes, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin, Serotonin, Serotonin Plasma Membrane Transport Proteins, Signal Transduction, Tissue Distribution, Transforming Growth Factor beta, Tryptophan Hydroxylase, Vascular Endothelial Growth Factor A
Show Abstract · Added January 28, 2014
Serotonin [5-hydroxytryptamine (5HT)] acts through multiple G protein-coupled 5-HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor-beta, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney.
1 Communities
2 Members
1 Resources
26 MeSH Terms
Renal cortical cyclooxygenase 2 expression is differentially regulated by angiotensin II AT(1) and AT(2) receptors.
Zhang MZ, Yao B, Cheng HF, Wang SW, Inagami T, Harris RC
(2006) Proc Natl Acad Sci U S A 103: 16045-50
MeSH Terms: Angiotensin II, Angiotensin II Type 2 Receptor Blockers, Animals, Bradykinin, Cell Line, Cyclooxygenase 2, Gene Expression Regulation, Enzymologic, Kidney Cortex, Male, Mice, Mice, Knockout, Nitric Oxide Synthase Type I, Rats, Receptor, Angiotensin, Type 1, Receptor, Angiotensin, Type 2, Sodium-Potassium-Chloride Symporters, Solute Carrier Family 12, Member 1
Show Abstract · Added December 10, 2013
Macula densa cyclooxygenase 2 (COX-2)-derived prostaglandins serve as important modulators of the renin-angiotensin system, and cross-talk exists between these two systems. Cortical COX-2 induction by angiotensin-converting enzyme (ACE) inhibitors or AT(1) receptor blockers (ARBs) suggests that angiotensin II may inhibit cortical COX-2 by stimulating the AT(1) receptor pathway. In the present studies we determined that chronic infusion of either hypertensive or nonhypertensive concentrations of angiotensin II attenuated cortical COX-2. Angiotensin II infusion reversed cortical COX-2 elevation induced by ACE inhibitors. However, we found that angiotensin II infusion further stimulated cortical COX-2 elevation induced by ARBs, suggesting a potential role for an AT(2) receptor-mediated pathway when the AT(1) receptor was inhibited. Both WT and AT(2) receptor knockout mice were treated for 7 days with either ACE inhibitors or ARBs. Cortical COX-2 increased to similar levels in response to ACE inhibition in both knockout and WT mice. In WT mice ARBs increased cortical COX-2 more than ACE inhibitors, and this stimulation was attenuated by the AT(2) receptor antagonist PD123319. In the knockout mice ARBs led to significantly less cortical COX-2 elevation, which was not attenuated by PD123319. PCR confirmed AT(1a) and AT(2) receptor expression in the cultured macula densa cell line MMDD1. Angiotensin II inhibited MMDD1 COX-2, and CGP42112A, an AT(2) receptor agonist, stimulated MMDD1 COX-2. In summary, these results demonstrate that macula densa COX-2 expression is oppositely regulated by AT(1) and AT(2) receptors and suggest that AT(2) receptor-mediated cortical COX-2 elevation may mediate physiologic effects that modulate AT(1)-mediated responses.
2 Communities
3 Members
0 Resources
17 MeSH Terms