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Nephrology

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Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis
Yingjian Li, … , Chuanyue Wu, Youhua Liu
Yingjian Li, … , Chuanyue Wu, Youhua Liu
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):503-516. https://doi.org/10.1172/JCI17913.
View: Text | PDF | Corrigendum

Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis

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Abstract

Under pathologic conditions, renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT), a phenotypic conversion that is believed to play a critical role in renal interstitial fibrogenesis. However, the underlying mechanism that governs this process remains largely unknown. Here we demonstrate that integrin-linked kinase (ILK) plays an important role in mediating tubular EMT induced by TGF-β1. TGF-β1 induced ILK expression in renal tubular epithelial cells in a time- and dose-dependent manner, which was dependent on intracellular Smad signaling. Forced expression of ILK in human kidney proximal tubular epithelial cells suppressed E-cadherin expression and induced fibronectin expression and its extracellular assembly. ILK also induced MMP-2 expression and promoted cell migration and invasion in Matrigel. Conversely, ectopic expression of a dominant-negative, kinase-dead form of ILK largely abrogated TGF-β1–initiated tubular cell phenotypic conversion. In vivo, ILK was markedly induced in renal tubular epithelia in mouse models of chronic renal diseases, and such induction was spatially and temporally correlated with tubular EMT. Moreover, inhibition of ILK expression by HGF was associated with blockade of tubular EMT and attenuation of renal fibrosis. These findings suggest that ILK is a critical mediator for tubular EMT and likely plays a crucial role in the pathogenesis of chronic renal fibrosis.

Authors

Yingjian Li, Junwei Yang, Chunsun Dai, Chuanyue Wu, Youhua Liu

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Collecting duct–specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance
Isabelle Rubera, … , Edith Hummler, Bernard C. Rossier
Isabelle Rubera, … , Edith Hummler, Bernard C. Rossier
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):554-565. https://doi.org/10.1172/JCI16956.
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Collecting duct–specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance

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Abstract

Aldosterone controls the final sodium reabsorption and potassium secretion in the kidney by regulating the activity of the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). ASDN consists of the last portion of the distal convoluted tubule (late DCT), the connecting tubule (CNT), and the collecting duct (CD) (i.e., the cortical CD [CCD] and the medullary CD [MCD]). It has been proposed that the control of sodium transport in the CCD is essential for achieving sodium and potassium balance. We have tested this hypothesis by inactivating the α subunit of ENaC in the CD but leaving ENaC expression in the late DCT and CNT intact. Under salt restriction or under aldosterone infusion, whole-cell voltage clamp of principal cells of CCD showed no detectable ENaC activity, whereas large amiloride-sensitive currents were observed in control littermates. The animals survive well and are able to maintain sodium and potassium balance, even when challenged by salt restriction, water deprivation, or potassium loading. We conclude that the expression of ENaC in the CD is not a prerequisite for achieving sodium and potassium balance in mice. This stresses the importance of more proximal nephron segments (late DCT/CNT) to achieve sodium and potassium balance.

Authors

Isabelle Rubera, Johannes Loffing, Lawrence G. Palmer, Gustavo Frindt, Nicole Fowler-Jaeger, Daniel Sauter, Tom Carroll, Andrew McMahon, Edith Hummler, Bernard C. Rossier

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A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis
Yufeng Huang, … , Ling Yu, Nancy A. Noble
Yufeng Huang, … , Ling Yu, Nancy A. Noble
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):379-388. https://doi.org/10.1172/JCI18038.
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A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis

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Abstract

In fibrotic renal disease, elevated TGF-β and angiotensin II lead to increased plasminogen activator inhibitor type 1 (PAI-1). PAI-1 appears to reduce glomerular mesangial matrix turnover by inhibiting plasminogen activators, thereby decreasing plasmin generation and plasmin-mediated matrix degradation. We hypothesized that therapy with a mutant human PAI-1 (PAI-1R) that binds to matrix vitronectin but does not inhibit plasminogen activators, would enhance plasmin generation, increase matrix turnover, and decrease matrix accumulation in experimental glomerulonephritis. Three experimental groups included normal, untreated disease control, and PAI-1R–treated nephritic rats. Plasmin generation by isolated day 3 glomeruli was dramatically decreased by 69%, a decrease that was reversed 43% (P < 0.02) by in vivo PAI-1R treatment. At day 6, animals treated with PAI-1R showed significant reductions in proteinuria (48%, P < 0.02), glomerular staining for periodic acid–Schiff positive material (33%, P < 0.02), collagen I (28%, P < 0.01), collagen III (34%, P < 0.01), fibronectin (48%, P < 0.01), and laminin (41%, P < 0.01), and in collagen I (P < 0.01) and fibronectin mRNA levels (P < 0.02). Treatment did not alter overexpression of TGF-β1 and PAI-1 mRNAs, although TGF-β1 protein was significantly reduced. These observations strongly support our hypothesis that PAI-1R reduces glomerulosclerosis by competing with endogenous PAI-1, restoring plasmin generation, inhibiting inflammatory cell infiltration, decreasing local TGF-β1 concentration, and reducing matrix accumulation.

Authors

Yufeng Huang, Masashi Haraguchi, Daniel A. Lawrence, Wayne A. Border, Ling Yu, Nancy A. Noble

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Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells
János Peti-Peterdi, … , Matthew D. Breyer, P. Darwin Bell
János Peti-Peterdi, … , Matthew D. Breyer, P. Darwin Bell
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):76-82. https://doi.org/10.1172/JCI18018.
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Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells

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Abstract

Macula densa (MD) cells express COX-2 and COX-2–derived PGs appear to signal the release of renin from the renal juxtaglomerular apparatus, especially during volume depletion. However, the synthetic machinery and identity of the specific prostanoid released from intact MD cells remains uncertain. In the present studies, a novel biosensor tool was engineered to directly determine whether MD cells release PGE2 in response to low luminal NaCl concentration ([NaCl]L). HEK293 cells were transfected with the Ca2+-coupled E-prostanoid receptor EP1 (HEK/EP1) and loaded with fura-2. HEK/EP1 cells produced a significant elevation in intracellular [Ca2+] ([Ca2+]i) by 29.6 ± 12.8 nM (n = 6) when positioned at the basolateral surface of isolated perfused MD cells and [NaCl]L was reduced from 150 mM to zero. HEK/EP1 [Ca2+]i responses were observed mainly in preparations from rabbits on a low-salt diet and were completely inhibited by either a selective COX-2 inhibitor or an EP1 antagonist, and also by 100 μM luminal furosemide. Also, 20-mM graduated reductions in [NaCl]L between 80 and 0 mM caused step-by-step increases in HEK/EP1 [Ca2+]i. Low-salt diet greatly increased the expression of both COX-2 and microsome-associated PGE synthase (mPGES) in the MD. These studies provide the first direct evidence that intact MD cells synthesize and release PGE2 during reduced luminal salt content and suggest that this response is important in the control of renin release and renal vascular resistance during salt deprivation.

Authors

János Peti-Peterdi, Peter Komlosi, Amanda L. Fuson, Youfei Guan, André Schneider, Zhonghua Qi, Reyadh Redha, Laszlo Rosivall, Matthew D. Breyer, P. Darwin Bell

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Mice deficient in α-actinin-4 have severe glomerular disease
Claudine H. Kos, … , Robert E. Gerszten, Martin R. Pollak
Claudine H. Kos, … , Robert E. Gerszten, Martin R. Pollak
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1683-1690. https://doi.org/10.1172/JCI17988.
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Mice deficient in α-actinin-4 have severe glomerular disease

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Abstract

Dominantly inherited mutations in ACTN4, which encodes α-actinin-4, cause a form of human focal and segmental glomerulosclerosis (FSGS). By homologous recombination in ES cells, we developed a mouse model deficient in Actn4. Mice homozygous for the targeted allele have no detectable α-actinin-4 protein expression. The number of homozygous mice observed was lower than expected under mendelian inheritance. Surviving mice homozygous for the targeted allele show progressive proteinuria, glomerular disease, and typically death by several months of age. Light microscopic analysis shows extensive glomerular disease and proteinaceous casts. Electron microscopic examination shows focal areas of podocyte foot-process effacement in young mice, and diffuse effacement and globally disrupted podocyte morphology in older mice. Despite the widespread distribution of α-actinin-4, histologic examination of mice showed abnormalities only in the kidneys. In contrast to the dominantly inherited human form of ACTN4-associated FSGS, here we show that the absence of α-actinin-4 causes a recessive form of disease in mice. Cell motility, as measured by lymphocyte chemotaxis assays, was increased in the absence of α-actinin-4. We conclude that α-actinin-4 is required for normal glomerular function. We further conclude that the nonsarcomeric forms of α-actinin (α-actinin-1 and α-actinin-4) are not functionally redundant. In addition, these genetic studies demonstrate that the nonsarcomeric α-actinin-4 is involved in the regulation of cell movement.

Authors

Claudine H. Kos, Tu Cam Le, Sumita Sinha, Joel M. Henderson, Sung Han Kim, Hikaru Sugimoto, Raghu Kalluri, Robert E. Gerszten, Martin R. Pollak

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Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome
Tamara Manuelian, … , Giuseppe Remuzzi, Peter F. Zipfel
Tamara Manuelian, … , Giuseppe Remuzzi, Peter F. Zipfel
Published April 15, 2003
Citation Information: J Clin Invest. 2003;111(8):1181-1190. https://doi.org/10.1172/JCI16651.
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Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome

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Abstract

Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent studies have identified a factor H–associated form of HUS, caused by gene mutations that cluster in the C-terminal region of the complement regulator factor H. Here we report how three mutations (E1172Stop, R1210C, and R1215G; each of the latter two identified in three independent cases from different, unrelated families) affect protein function. All three mutations cause reduced binding to the central complement component C3b/C3d to heparin, as well as to endothelial cells. These defective features of the mutant factor H proteins explain progression of endothelial cell and microvascular damage in factor H–associated genetic HUS and indicate a protective role of factor H for tissue integrity during thrombus formation.

Authors

Tamara Manuelian, Jens Hellwage, Seppo Meri, Jessica Caprioli, Marina Noris, Stefan Heinen, Mihaly Jozsi, Hartmut P.H. Neumann, Giuseppe Remuzzi, Peter F. Zipfel

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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia
Sharon E. Maynard, … , Vikas P. Sukhatme, S. Ananth Karumanchi
Sharon E. Maynard, … , Vikas P. Sukhatme, S. Ananth Karumanchi
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):649-658. https://doi.org/10.1172/JCI17189.
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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

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Abstract

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

Authors

Sharon E. Maynard, Jiang-Yong Min, Jaime Merchan, Kee-Hak Lim, Jianyi Li, Susanta Mondal, Towia A. Libermann, James P. Morgan, Frank W. Sellke, Isaac E. Stillman, Franklin H. Epstein, Vikas P. Sukhatme, S. Ananth Karumanchi

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Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo
Sydney Tang, … , Tak Mao Chan, Kar Neng Lai
Sydney Tang, … , Tak Mao Chan, Kar Neng Lai
Published February 15, 2003
Citation Information: J Clin Invest. 2003;111(4):515-527. https://doi.org/10.1172/JCI16079.
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Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo

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Abstract

Renal tubulointerstitial injury is characterized by inflammatory cell infiltrate; however, the stimuli for leukocyte recruitment are not fully understood. IL-8 is a potent chemokine produced by proximal tubular epithelial cells (PTECs). Whether nephrotic proteins stimulate tubular IL-8 expression remains unknown. Acute exposure of human PTECs to albumin induced IL-8 gene and protein expression time- and dose-dependently. Apical albumin predominantly stimulated basolateral IL-8 secretion. Electrophoretic mobility shift assay demonstrated nuclear translocation of NF-κB, and the p65/p50 subunits were activated. NF-κB activation and IL-8 secretion were attenuated by the NF-κB inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H2O2 stimulated NF-κB translocation and IL-8 secretion. Albumin-induced ROS generation, NF-κB activation, and IL-8 secretion were endocytosis- and PKC-dependent as these downstream events were abrogated by the PI3K inhibitors LY294002 and wortmannin, and the PKC inhibitors GF109203X and staurosporin, respectively. In vivo, IL-8 mRNA expression was localized by in situ hybridization to the proximal tubules in nephrotic kidney tissues. The intensity of IL-8 immunostaining was higher in nephrotic than non-nephrotic subjects. In conclusion, albumin is a strong stimulus for tubular IL-8 expression, which occurs via NF-κB–dependent pathways through PKC activation and ROS generation.

Authors

Sydney Tang, Joseph C.K. Leung, Katsushige Abe, Kwok Wah Chan, Loretta Y.Y. Chan, Tak Mao Chan, Kar Neng Lai

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Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy
Junwei Yang, … , Kari Nejak, Youhua Liu
Junwei Yang, … , Kari Nejak, Youhua Liu
Published November 15, 2002
Citation Information: J Clin Invest. 2002;110(10):1525-1538. https://doi.org/10.1172/JCI16219.
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Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy

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Abstract

Research Article

Authors

Junwei Yang, Ryan W. Shultz, Wendy M. Mars, Rodney E. Wegner, Yingjian Li, Chunsun Dai, Kari Nejak, Youhua Liu

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Impaired renal Na+ retention in the sgk1-knockout mouse
Peer Wulff, … , Florian Lang, Dietmar Kuhl
Peer Wulff, … , Florian Lang, Dietmar Kuhl
Published November 1, 2002
Citation Information: J Clin Invest. 2002;110(9):1263-1268. https://doi.org/10.1172/JCI15696.
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Impaired renal Na+ retention in the sgk1-knockout mouse

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Abstract

Research Article

Authors

Peer Wulff, Volker Vallon, Dan Yang Huang, Harald Völkl, Fang Yu, Kerstin Richter, Martina Jansen, Michaela Schlünz, Karin Klingel, Johannes Loffing, Gunther Kauselmann, Michael R. Bösl, Florian Lang, Dietmar Kuhl

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Local TNF mediates free cholesterol–dependent podocyte injury
In this episode, Alessia Fornoni reveals that TNF promotes free cholesterol–dependent podocyte apoptosis via an NFATc1/ ABCA1-dependent mechanism.
Published August 2, 2016
Author's TakeNephrology

Anti-THSD7A is a bona fide culprit in membranous nephropathy
Nicola M. Tomas, Elion Hoxha, and colleagues provide evidence that anti-THSD7A antibodies promote the development of membranous nephropathy...
Published May 23, 2016
Scientific Show StopperNephrology

Identifying sporadic focal segmental glomerulosclerosis-associated genes
Haiyang Yu, Mykyta Artomov, Sebastian Brähler and colleagues demonstrate the genetic contribution to the development of focal segmental glomerulosclerosis...
Published February 22, 2016
Scientific Show StopperNephrology

DNA replication stress linked to ciliopathies
Gisela Slaats and colleagues reveal that ciliopathy syndrome-associated mutations in CEP290 result in replication errors and DNA damage…
Published August 24, 2015
Scientific Show StopperNephrology

Nephrotic syndrome-associated mutations
Heon Yung Gee, Fujian Zhang, and colleagues reveal that mutations in KANK family genes underlie podocyte dysfunction and are associated with nephrotic syndrome…
Published May 11, 2015
Scientific Show StopperNephrology

Podocyte macropinocytosis
Jun-Jae Chung, Tobias B. Huber, Markus Gödel, and colleagues show that albumin-bound free fatty acids increase fluid-phase uptake in podocytes…
Published April 27, 2015
Scientific Show StopperNephrology

A network of diuretic resistance
Richard Grimm and colleagues use a systems biology approach to uncover mechanisms of renal compensation that lead to diuretic resistance…
Published April 20, 2015
Scientific Show StopperNephrology

KIM-1 protects the kidney after injury
Li Yang, Craig Brooks, and colleagues at Harvard Medical School demonstrate that KIM-1-mediated phagocytosis of apoptotic cells dampens inflammatory responses after kidney injury.. .
Published March 9, 2015
Scientific Show StopperNephrology

Protection against acute kidney injury
Marina Morigi and colleagues demonstrate that sirtuin 3 expression improves survival in a murine model of acute kidney injury...
Published January 20, 2015
Scientific Show StopperNephrology

Helping polycysin-1 reach the surface
Vladimir Gainullin and colleagues reveal that polycystin-2 is required for maturation and surface localization of polycystin-1…
Published January 9, 2015
Scientific Show StopperNephrology
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