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您现在的位置：首页>美国卫生研究院文献>American Journal of Physiology - Renal Physiology

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  • 刊频： Twice monthly, Jan. 2012-
  • NLM标题： Am J Physiol Renal Physiol
  • iso缩写： -
  • ISSN： -

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  • 1.

    【2hr】The macula densa prorenin receptor is essential in renin release and blood pressure control

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    机译 黄斑densa prorenin受体在释放肾素和控制血压中至关重要
    摘要：The prorenin receptor (PRR) was originally proposed to be a member of the renin-angiotensin system (RAS); however, recent work questioned their association. The present paper describes a functional link between the PRR and RAS in the renal juxtaglomerular apparatus (JGA), a classic anatomical site of the RAS. PRR expression was found in the sensory cells of the JGA, the macula densa (MD), and immunohistochemistry-localized PRR to the MD basolateral cell membrane in mouse, rat, and human kidneys. MD cell PRR activation led to MAP kinase ERK1/2 signaling and stimulation of PGE2 release, the classic pathway of MD-mediated renin release. Exogenous renin or prorenin added to the in vitro microperfused JGA-induced acute renin release, which was inhibited by removing the MD or by the administration of a PRR decoy peptide. To test the function of MD PRR in vivo, we established a new mouse model with inducible conditional knockout (cKO) of the PRR in MD cells based on neural nitric oxide synthase-driven Cre-lox recombination. Deletion of the MD PRR significantly reduced blood pressure and plasma renin. Challenging the RAS by low-salt diet + captopril treatment caused further significant reductions in blood pressure, renal renin, cyclooxygenase-2, and microsomal PGE synthase expression in cKO vs. wild-type mice. These results suggest that the MD PRR is essential in a novel JGA short-loop feedback mechanism, which is integrated within the classic MD mechanism to control renin synthesis and release and to maintain blood pressure.
  • 2.

    【2hr】Chronic lithium treatment induces novel patterns of pendrin localization and expression

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    机译 慢性锂治疗诱导Pendrin定位和表达的新模式
    摘要：Prolonged lithium treatment is associated with various renal side effects and is known to induce inner medullary collecting duct (IMCD) remodeling. In animals treated with lithium, the fraction of intercalated cells (ICs), which are responsible for acid-base homeostasis, increases compared with renal principal cells (PCs). To investigate the intricacies of lithium-induced IMCD remodeling, male Sprague-Dawley rats were fed a lithium-enriched diet for 0,1, 2, 3, 6, 9, or 12 wk. Urine osmolality was decreased at 1 wk, and from 2 to 12 wk, animals were severely polyuric. After 6 wk of lithium treatment, approximately one-quarter of the cells in the initial IMCD expressed vacuolar H+-ATPase, an IC marker. These cells were localized in portions of the inner medulla, where ICs are not normally found. Pendrin, a Cl−/HCO3− exchanger, is normally expressed only in two IC subtypes found in the convoluted tubule, the cortical collecting duct, and the connecting tubule. At 6 wk of lithium treatment, we observed various patterns of pendrin localization and expression in the rat IMCD, including a novel phenotype wherein pendrin was coexpressed with aquaporin-4. These observations collectively suggest that renal IMCD cell plasticity may play an important role in lithium-induced IMCD remodeling.
  • 3.

    【2hr】Mechanism and Treatment of Renal Fibrosis: Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice

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    机译 肾纤维化的机制和治疗：在小鼠单侧输尿管梗阻后EMT相关肾纤维化发展需要波形蛋白表达
    摘要：Most renal transplants ultimately fail secondary to chronic allograft nephropathy (CAN). Vimentin (vim) is a member of the intermediate filament family of proteins and has been shown to be important in the development of CAN. One of the pathways leading to chronic renal fibrosis after transplant is thought to be epithelial to mesenchymal transition (EMT). Even though vim expression is one of the main steps of EMT, it is unknown whether vim expression is required for EMT leading to renal fibrosis and allograft loss. To this end, the role of vim in renal fibrosis was determined via unilateral ureteral obstruction (UUO) in vim knockout mice (129 svs6 vim −/−). Following UUO, kidneys were recovered and analyzed via Western blotting, immunofluorescence, and transcriptomics. Cultured human proximal renal tubular (HK-2) cells were subjected to lentiviral-driven inhibition of vim expression and then treated with transforming growth factor (TGF)-β to undergo EMT. Immunoblotting as well as wound healing assays were used to determine development of EMT. Western blotting analyses of mice undergoing UUO reveal increased levels of vim soon after UUO. As expected, interstitial collagen deposition increased in control mice following UUO but decreased in vim −/− kidneys. Immunofluorescence analyses also revealed altered localization of β-catenin in vim −/− mice undergoing UUO without significant changes in mRNA levels. However, RNA sequencing revealed a decrease in β-catenin-dependent genes in vim −/− kidneys. Finally, vim-silenced HK-2 cell lines undergoing EMT were shown to have decreased cellular migration during wound healing. We conclude that vim inhibition decreases fibrosis following UUO by possibly altering β-catenin localization and downstream signaling.
  • 4.

    【2hr】Mechanism and Treatment of Renal Fibrosis: Sphingosine-1-phosphate pathway in renal fibrosis

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    机译 肾纤维化的机制和治疗：鞘氨醇-1-磷酸途径在肾纤维化中的作用
    摘要：Renal fibrosis is defined as the excessive deposition and modification of extracellular matrix (ECM) in the renal parenchyma in response to injury and inflammation, resulting in renal function loss. This condition is common to many chronic kidney diseases occurring under diverse pathological conditions, such as diabetic and hypertensive nephropathy. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in the regulation of cardiovascular functions and the pathogenesis of various cardiovascular diseases. S1P has also been considered an important regulator of fibrotic diseases, playing significant roles in the differentiation of fibroblasts to myofibroblasts and in the induction of inflammatory responses during the early stages of fibrotic diseases. This minireview summarizes recent research findings regarding the importance of the sphingosine kinase-1-S1P-S1P receptor axis and its interactions with other classic fibrotic signaling pathways and the immune inflammatory response to reveal novel therapeutic targets for the treatment or prevention of renal fibrosis.
  • 5.

    【2hr】Molecular Mechanism of Renal Tubule Transport: Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney

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    机译 肾小管运输的分子机制：NBCe1（SLC4A4）B剪接变体在小鼠肾脏中的表达
    摘要：Sodium-coupled bicarbonate transporters are critical for renal electrolyte transport. The electrogenic, sodium-coupled bicarbonate cotransporter, isoform 1 (NBCe1), encoded by the SLC4A4 geneencoded by the SLC4A4 gene has five multiple splice variants; the A splice variant, NBCe1-A, is the primary basolateral bicarbonate transporter in the proximal convoluted tubule. This study’s purpose was to determine if there is expression of additional NBCe1 splice variants in the mouse kidney, their cellular distribution, and their regulation by metabolic acidosis. In wild-type mice, an antibody reactive only to NBCe1-A showed basolateral immunolabel only in cortical proximal tubule (PT) segments, whereas an antibody reactive to all NBCe1 splice variants (pan-NBCe1) showed basolateral immunolabel in PT segments in both the cortex and outer medulla. In mice with NBCe1-A deletion, the pan-NBCe1 antibody showed basolateral PT immunolabel in both the renal cortex and outer stripe of the outer medulla, and immunoblot analysis showed expression of a ~121-kDa protein. RT-PCR of mRNA from NBCe1-A knockout mice directed at splice variant-specific regions showed expression of only NBCe1-B mRNA. In wild-type kidney, RT-PCR confirmed expression of mRNA for the NBCe1-B splice variant and absence of mRNA for the C, D, and E splice variants. Finally, exogenous acid loading increased expression in the proximal straight tubule in the outer stripe of the outer medulla. These studies demonstrate that the NBCe1-B splice variant is present in the PT, and its expression increases in response to exogenous acid loading, suggesting it participates in the PT contribution to acid-base homeostasis.
  • 6.

    【2hr】Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells

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    机译 Biliverdin Reasease-A的缺失促进小鼠近端小管细胞的脂质蓄积和脂毒性
    摘要：Obesity and increased lipid availability have been implicated in the development and progression of chronic kidney disease. One of the major sites of renal lipid accumulation is in the proximal tubule cells of the kidney, suggesting that these cells may be susceptible to lipotoxicity. We previously demonstrated that loss of hepatic biliverdin reductase A (BVRA) causes fat accumulation in livers of mice on a high-fat diet. To determine the role of BVRA in mouse proximal tubule cells, we generated a CRISPR targeting BVRA for a knockout in mouse proximal tubule cells (BVRA KO). The BVRA KO cells had significantly less metabolic potential and mitochondrial respiration, which was exacerbated by treatment with palmitic acid, a saturated fatty acid. The BVRA KO cells also showed increased intracellular triglycerides which were associated with higher fatty acid uptake gene cluster of differentiation 36 as well as increased de novo lipogenesis as measured by higher neutral lipids. Additionally, neutrophil gelatinase-associated lipocalin 1 expression, annexin-V FITC staining, and lactate dehydrogenase assays all demonstrated that BVRA KO cells are more sensitive to palmitic acid-induced lipotoxicity than wild-type cells. Phosphorylation of BAD which plays a role in cell survival pathways, was significantly reduced in palmitic acid-treated BVRA KO cells. These data demonstrate the protective role of BVRA in proximal tubule cells against saturated fatty acid-induced lipotoxicity and suggest that activating BVRA could provide a benefit in protecting from obesity-induced kidney injury.
  • 7.

    【2hr】Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

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    机译 2型糖尿病患者尿中血管紧张素转换酶2和中性溶酶升高
    摘要：Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1–7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.
  • 8.

    【2hr】Predicted effect of circadian clock modulation of NHE3 of a proximal tubule cell on sodium transport

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    机译 预测近端小管细胞NHE3的昼夜节律对钠转运的影响
    摘要：Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na+-H+ exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins. The model predicts the rhythmic oscillations in NHE3 activity, which gives rise to significant daily fluctuations in Na+ and water transport of the proximal tubule cell. Additionally, the model predicts that 1) mutation in period 2 (Per2) or cryptochrome 1 (Cry1) preserves the circadian rhythm and modestly raises Na+ reabsorption; 2) mutation in Bmal1 or CLOCK eliminates the circadian rhythm and modestly lowers Na+ reabsorption; 3) mutation in Rev-Erb or ROR-related orphan receptor (Ror) has minimal impact on the circadian oscillations. The model represents the first step in building a tool set aimed at increasing our understanding of how the molecular clock affects renal ion transport and renal function, which likely has important implications for kidney disease.
  • 9.

    【2hr】A zebrafish model of infection-associated acute kidney injury

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    机译 与感染相关的急性肾损伤的斑马鱼模型
    摘要：Sepsis-associated acute kidney injury (S-AKI) independently predicts mortality among critically ill patients. The role of innate immunity in this process is unclear, and there is an unmet need for S-AKI models to delineate the pathophysiological response. Mammals and zebrafish (Danio rerio) share a conserved nephron structure and homologous innate immune systems, making the latter suitable for S-AKI research. We introduced Edwardsiella tarda to the zebrafish. Systemic E. tarda bacteremia resulted in sustained bacterial infection and dose-dependent mortality. A systemic immune reaction was characterized by increased mRNA expressions of il1b, tnfa, tgfb1a, and cxcl8-l1 (P < 0.0001, P < 0.001, P < 0.001, and P < 0.01, respectively). Increase of host stress response genes ccnd1 and tp53 was observed at 24 h postinjection (P < 0.0001 and P < 0.05, respectively). Moderate E. tarda infection induced zebrafish mortality of over 50% in larvae and 20% in adults, accompanied by pericardial edema in larvae and renal dysfunction in both larval and adult zebrafish. Expression of AKI markers insulin-like growth factor-binding protein-7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP-2), and kidney injury molecule-1 (KIM-1) was found to be significantly increased in the septic animals at the transcription level (P < 0.01, P < 0.05, and P < 0.05) and in nephric tubules compared with noninfected animals. In conclusion, we established a zebrafish model of S-AKI induced by E. tarda injection, with both larval and adult zebrafish showing nephron injury in the setting of infection.
  • 10.

    【2hr】Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8

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    机译 酪蛋白激酶1ε和1α作为多囊性肾脏疾病的新角色和（R）-roscovitine和（S）-CR8的机制靶标
    摘要：Following the discovery of (R)-roscovitine’s beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1α isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates.
  • 11.

    【2hr】Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease

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    机译 鉴定多囊肾疾病中IL-13和STAT6信号转导的靶标
    摘要：Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening, highly prevalent monogenic disease caused by mutations in polycystin-1 (PC1) in 85% of patients. We have previously identified a COOH-terminal cleavage fragment of PC1, PC1-p30, which interacts with the transcription factor STAT6 to promote transcription. STAT6 is aberrantly active in PKD mouse models and human ADPKD, and genetic removal or pharmacological inhibition of STAT6 attenuates disease progression. High levels of IL-13, a STAT6-activating cytokine, are found in the cyst fluid of PKD mouse models and increased IL-13 receptors in ADPKD patient tissue, suggesting that a positive feedback loop exists between IL-13 and STAT6 is activated in cystic epithelial cells and contributes to disease progression. In this study, we aimed to identify genes aberrantly regulated by STAT6 to better understand how increased IL-13/STAT6 signaling may contribute to PKD progression. We demonstrate that the expression of periostin, galectin-3, and IL-24 is upregulated in various forms of PKD and that their aberrant regulation is mediated by IL-13 and STAT6 activity. Periostin and galectin-3 have previously been implicated in PKD progression. We support these findings by showing that periostin expression is increased after IL-13 treatment in kidney epithelial cells, that galectin-3 expression is increased after injecting IL-13 in vivo and that IL-24 expression is upregulated by both IL-13 treatment and PC1-p30 overexpression in mouse and human kidney cells. Overall, these findings provide insight into the possible mechanisms by which increased IL-13/STAT6 signaling contributes to PKD progression and suggest potential therapeutic targets.
  • 12.

    【2hr】Translational Physiology: A MAPP Network study: overexpression of tumor necrosis factor-α in mouse urothelium mimics interstitial cystitis

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    机译 翻译生理学：MAPP网络研究：小鼠尿路上皮中肿瘤坏死因子-α的过度表达模拟间质性膀胱炎
    摘要：Interstitial cystitis/bladder pain syndrome is a chronic bladder condition associated with pain and voiding dysfunction that is often regarded as a neurogenic cystitis. Patient symptoms are correlated with the presence of urothelial lesions. We previously characterized a murine neurogenic cystitis model that recapitulates mast cell accumulation and urothelial lesions, and these events were dependent on TNF. To further explore the role of TNF in bladder inflammation and function, we generated a transgenic mouse model with chronic TNF overexpression in urothelium under the control of the uroplakin II (UPII) promoter. Transgenic mouse lines were maintained by backcross onto wild-type C57BL/6J mice and evaluated for pelvic tactile allodynia as a measure of visceral pain, urinary function, and urothelial lesions. TNF mRNA and protein were expressed at greater levels in bladders of UPII-TNF mice than in those of wild-type mice. UPII-TNF mice showed significantly increased urinary frequency and decreased void volume. UPII-TNF mice had increased urothelial apoptosis and loss of urothelial integrity consistent with urothelial lesions. Overexpression of TNF was also associated with pelvic tactile allodynia. Consistent with these findings, UPII-TNF mice exhibited increased bladder afferent activity in response to stretch ex vivo. In summary, UPII-TNF mice display significant pelvic pain, voiding dysfunction, urothelial lesions, and sensory input. Thus UPII-TNF mice are a model for characterizing mechanisms of interstitial cystitis symptoms and evaluating therapies.
  • 13.

    【2hr】VEGF therapy for the kidney: emerging strategies

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    机译 肾脏的VEGF治疗：新兴策略
    摘要：Renovascular disease (RVD), which is prevalent in the elderly, significantly increases cardiovascular risk and can progressively deteriorate renal function. The loss of renal function in patients with RVD is associated with a progressive dysfunction, damage, and loss of renal microvessels, which can be combined with decreased renal bioavailability of vascular endothelial growth factor (VEGF) and a defective vascular repair and proliferation. This association has been the impetus for recent efforts that have focused on developing methods to stop the progression of renal injury by protecting the renal microvasculature. This mini-review focuses on recent studies supporting potential applications of VEGF therapy for the kidney and discusses underlying mechanisms of renoprotection.
  • 14.

    【2hr】Mechanisms of altered renal sodium handling in age-related hypertension

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    机译 老年高血压患者肾脏钠处理改变的机制
    摘要：The prevalence of hypertension rises with age to approximately two out of three adults over the age of 60 in the United States. Although the mechanisms underlying age-related hypertension are incompletely understood, sodium homeostasis is critical to the long-term regulation of blood pressure and there is strong evidence that aging is associated with alterations in renal sodium handling. This minireview focuses on recent advancements in our understanding of the vascular, neurohumoral, and renal mechanisms that influence sodium homeostasis and promote age-related hypertension.
  • 15.

    【2hr】Molecular Mechanism of Renal Tubule Transport: With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo

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    机译 肾小管运输的分子机制：没有赖氨酸激酶4调节体内钾钠2氯化物cotransporter活性。
    摘要：With no lysine kinase 4 (WNK4) is essential to activate the thiazide-sensitive NaCl cotransporter (NCC) along the distal convoluted tubule, an effect central to the phenotype of familial hyperkalemic hypertension. Although effects on potassium and sodium channels along the connecting and collecting tubules have also been documented, WNK4 is typically believed to have little role in modulating sodium chloride reabsorption along the thick ascending limb of the loop of Henle. Yet wnk4−/− mice (knockout mice lacking WNK4) do not demonstrate the hypocalciuria typical of pure distal convoluted tubule dysfunction. Here, we tested the hypothesis that WNK4 also modulates bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) function along the thick ascending limb. We confirmed that wnk4−/− mice are hypokalemic and waste sodium chloride, but are also normocalciuric. Results from Western blots suggested that the phosphorylated forms of both NCC and NKCC2 were in lower abundance in wnk4−/− mice than in controls. This finding was confirmed by immunofluorescence microscopy. Although the initial response to furosemide was similar in wnk4−/− mice and controls, the response was lower in the knockout mice when reabsorption along the distal convoluted tubule was inhibited. Using HEK293 cells, we showed that WNK4 increases the abundance of phosphorylated NKCC2. More supporting evidence that WNK4 may modulate NKCC2 emerges from a mouse model of WNK4-mediated familial hyperkalemic hypertension in which more phosphorylated NKCC2 is present than in controls. These data indicate that WNK4, in addition to modulating NCC, also modulates NKCC2, contributing to its physiological function in vivo.
  • 16.

    【2hr】Molecular Mechanism of Renal Tubule Transport: α-Ketoglutarate stimulates pendrin-dependent Cl− absorption in the mouse CCD through protein kinase C

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    机译 肾小管运输的分子机制：α-酮戊二酸通过蛋白激酶C刺激小鼠CCD中Pendrin依赖的Cl-吸收
    摘要：α-Ketoglutarate (α-KG) is a citric acid cycle intermediate and a glutamine catabolism product. It is also the natural ligand of 2-oxoglutarate receptor 1 (OXGR1), a Gq protein-coupled receptor expressed on the apical membrane of intercalated cells. In the cortical collecting duct (CCD), Cl−/HCO3− exchange increases upon α-KG binding to the OXGR1. To determine the signaling pathway(s) by which α-KG stimulates Cl− absorption, we examined α-KG-stimulated Cl− absorption in isolated perfused mouse CCDs. α-KG increased electroneutral Cl− absorption in CCDs from wild-type mice but had no effect on Cl− absorption in pendrin knockout mice. Because Gq protein-coupled receptors activate PKC, we hypothesized that α-KG stimulates Cl− absorption through PKC. If so, PKC agonists should mimic, whereas PKC inhibitors should abolish, α-KG-stimulated Cl− absorption. Like α-KG, PKC agonist (phorbol-12,13-dibutyrate, 500 nM) application increased Cl− absorption in wild-type but not in pendrin null CCDs. Moreover, PKC inhibitors (2.5 mM GF109203X and 20 nM calphostin C), Ca2+ chelators (BAPTA, 10–20 μM), or PKC-α or -δ gene ablation eliminated α-KG-stimulated Cl− absorption. We have shown that STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) gene ablation increases urinary α-KG excretion, renal pendrin abundance, and CCD Cl− absorption. However, in SPAK null CCDs, Cl− absorption was not activated further by luminal α-KG application nor was Cl− absorption reduced with the PKC inhibitor . Thus SPAK gene ablation likely acts through a PKC-independent pathway to produce a chronic adaptive increase in pendrin function. In conclusion, α-KG stimulates pendrin-dependent Cl−/HCO3− exchange through a mechanism dependent on PKC and Ca2+ that involves PKC-α and PKC-δ.
  • 17.

    【2hr】Lack of contribution of nitric oxide synthase to cholinergic vasodilation in murine renal afferent arterioles

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    机译 一氧化氮合酶对鼠肾传入小动脉胆碱能血管舒张作用的缺乏
    摘要：We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation was functionally determined in kidneys of wild-type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood-perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, Nω-nitro-l-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N5-(1-imino-3-butenyl)-l-ornithine (VNIO). Acetylcholine (0.1 mM) produced a significant vasoconstriction in afferent arterioles of AT1A/AT1B mice (−10.9 ± 5.1%) and no changes in afferent arteriolar diameters of AT1A knockout mice. NLA (0.01–1 mM) or VNIO (0.01–1 μM) induced significant dose-dependent vasoconstrictions (−19.8 ± 4.0% 1 mM NLA; −7.8 ± 3.5% 1 μM VNIO) in afferent arterioles of kidneys of wild-type mice. VNIO had no effect on afferent arteriole diameters of AT1A knockout or AT1A/AT1B knockout mice, suggesting nonfunctional neuronal nitric oxide synthase. These data indicate that acetylcholine produces a significant renal afferent arteriole vasodilation independently of nitric oxide synthases in wild-type mice. AT1A receptors are essential for the manifestation of renal afferent arteriole responses to neuronal nitric oxide synthase-mediated nitric oxide release.
  • 18.

    【2hr】Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice

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    机译 Ncoa7基因的靶向缺失导致小鼠远端肾小管酸中毒不完全
    摘要：We recently reported that nuclear receptor coactivator 7 (Ncoa7) is a vacuolar proton pumping ATPase (V-ATPase) interacting protein whose function has not been defined. Ncoa7 is highly expressed in the kidney and partially colocalizes with the V-ATPase in collecting duct intercalated cells (ICs). Here, we hypothesized that targeted deletion of the Ncoa7 gene could affect V-ATPase activity in ICs in vivo. We tested this by analyzing the acid-base status, major electrolytes, and kidney morphology of Ncoa7 knockout (KO) mice. We found that Ncoa7 KO mice, similar to Atp6v1b1 KOs, did not develop severe distal renal tubular acidosis (dRTA), but they exhibited a persistently high urine pH and developed hypobicarbonatemia after acid loading with ammonium chloride. Conversely, they did not develop significant hyperbicarbonatemia and alkalemia after alkali loading with sodium bicarbonate. We also found that ICs were larger and with more developed apical microvilli in Ncoa7 KO compared with wild-type mice, a phenotype previously associated with metabolic acidosis. At the molecular level, the abundance of several V-ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 was significantly reduced in medullary ICs of Ncoa7 KO mice, suggesting that Ncoa7 is important for maintaining high levels of these proteins in the kidney. We conclude that Ncoa7 is involved in IC function and urine acidification in mice in vivo, likely through modulating the abundance of V-ATPase and other key acid-base regulators in the renal medulla. Consequently, mutations in the NCOA7 gene may also be involved in dRTA pathogenesis in humans.
  • 19.

    【2hr】The tale of two (distal nephron) cell types

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    机译 两种（远端肾单位）细胞类型的故事
    摘要：
  • 20.

    【2hr】Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis

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    机译 局灶节段性肾小球硬化症的机械挑战和细胞骨架损伤
    摘要：Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.
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