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D Prabhu Y, Bhati M, Vellingiri B, Valsala Gopalakrishnan A. The effect of γ-linolenic acid on Polycystic Ovary Syndrome associated Focal Segmental Glomerulosclerosis via TGF-β pathway. Life Sci 2021; 276:119456. [PMID: 33811895 DOI: 10.1016/j.lfs.2021.119456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/21/2021] [Accepted: 03/29/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND In recent years, female infertility from Polycystic Ovary Syndrome (PCOS) has gained scientific interest. PCOS alters the metabolic and endocrine functioning in females. The elevation in androgens can damage the androgen receptors present on the kidney giving rise to renal disorders like Focal Segmental Glomerulosclerosis (FSGS). Transforming Growth Factor Beta (TGF-β) in the ovary is activated by activin for Follicle Stimulating Hormone (FSH) secretion and in the kidney by thrombospondin 1 (TSP1) for cell growth and apoptosis. Studies show that gamma-linolenic acid (GLA) effectively treats breast cancer, eczema, inflammatory conditions and PCOS. AIM The study aimed to find out the possibility of FSGS development in PCOS and to understand the effect of GLA on FSGS via the TGF-β pathway. METHOD To carry out the study, the dehydroepiandrosterone (DHEA) induced PCOS model was used. Three groups namely vehicle control, DHEA, and DHEA+GLA, were used with six animals in each. TGF-β1, TGF-β2, and TSP1 genes were studied using real-time PCR. RESULTS The study showed an increase in the level of renal fibrosis biomarker, TSP1, in the DHEA group, which was further decreased by an anti-inflammatory agent, GLA. The TGF-β1 and TGF-β2 genes associated with the TGF-β pathway were seen to be increased in DHEA-induced PCOS rats which showed a possible relation between the two conditions. CONCLUSION The study shows a possible development of renal fibrosis in the DHEA-induced PCOS model. The GLA might act as a ligand to regulate TGF-β signaling in glomerulosclerosis in a DHEA-induced PCOS model.
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Affiliation(s)
- Yogamaya D Prabhu
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Monica Bhati
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
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Ha TS, Ha DS. Ginseng Total Saponin Attenuates Podocyte Apoptosis Induced by Diabetic Conditions Through the Recovery of CD2-Associated Protein. J Med Food 2019; 22:170-177. [PMID: 30601089 DOI: 10.1089/jmf.2017.4139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
CD2-associated protein (CD2AP), an adaptor protein, plays several important roles in podocyte function, linking slit diaphragms to actin-based cytoskeleton and sending survival signals. Here, we investigated whether ginseng total saponin (GTS) had a protective role in the changes of podocyte CD2AP protein and podocyte apoptosis under in vitro diabetic conditions. Conditionally immortalized mouse podocytes cultured with normal glucose (5 mM) or high glucose (30 mM) and with or without advanced glycosylation end products were treated with GTS. We found that CD2AP co-localized with the F-actin fibers in podocyte cytoplasm using confocal imaging; however, diabetic conditions caused the podocytes to diminish and conglomerate CD2AP stainings in the peripheral cytoplasm, which were recovered by GTS. Diabetic conditions also suppressed CD2AP protein levels at 6 and 24 h in western blotting. These phenotypical changes of CD2AP protein were mitigated by GTS. Diabetic conditions also induced podocyte apoptosis at 24 h, which were attenuated by GTS. These findings provide a novel mechanism that diabetic conditions induce quantitative and qualitative changes of podocyte CD2AP protein and apoptosis, which would be restored by GTS.
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Affiliation(s)
- Tae-Sun Ha
- 1 Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, Korea.,2 Department of Pediatrics, Chungbuk National University Hospital, Cheongju, Korea
| | - Dong-Soo Ha
- 3 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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Daehn IS. Glomerular Endothelial Cell Stress and Cross-Talk With Podocytes in Early [corrected] Diabetic Kidney Disease. Front Med (Lausanne) 2018; 5:76. [PMID: 29629372 PMCID: PMC5876248 DOI: 10.3389/fmed.2018.00076] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/07/2018] [Indexed: 12/11/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the major causes of morbidity and mortality in diabetic patients and also the leading single cause of end-stage renal disease in the United States. A large proportion of diabetic patients develop DKD and others don't, even with comparable blood glucose levels, indicating a significant genetic component of disease susceptibility. The glomerulus is the primary site of diabetic injury in the kidney, glomerular hypertrophy and podocyte depletion are glomerular hallmarks of progressive DKD, and the degree of podocyte loss correlates with severity of the disease. We know that chronic hyperglycemia contributes to both microvascular and macrovascular complications, as well as podocyte injury. We are beginning to understand the role of glomerular endothelial injury, as well as the involvement of reactive oxygen species and mitochondrial stress, which play a direct role in DKD and in other diabetic complications. There is, however, a gap in our knowledge that links genetic susceptibility to early molecular mechanisms and proteinuria in DKD. Emerging research that explores glomerular cell's specific responses to diabetes and cell cross-talk will provide mechanistic clues that underlie DKD and provide novel avenues for therapeutic intervention.
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Affiliation(s)
- Ilse Sofia Daehn
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York City, NY, United States
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CD2-associated protein/phosphoinositide 3-kinase signaling has a preventive role in angiotensin II-induced podocyte apoptosis. Int J Biochem Cell Biol 2016; 79:370-381. [DOI: 10.1016/j.biocel.2016.08.042] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 08/19/2016] [Accepted: 08/29/2016] [Indexed: 01/13/2023]
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Raij L, Tian R, Wong JS, He JC, Campbell KN. Podocyte injury: the role of proteinuria, urinary plasminogen, and oxidative stress. Am J Physiol Renal Physiol 2016; 311:F1308-F1317. [PMID: 27335373 DOI: 10.1152/ajprenal.00162.2016] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/13/2016] [Indexed: 12/19/2022] Open
Abstract
Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap-/- model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O2-) that promotes endothelin-1 synthesis. Plg via O2- also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a "second hit" in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.
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Affiliation(s)
- Leopoldo Raij
- Renal and Hypertension Division, University of Miami Miller School of Medicine, Miami, Florida; .,Nephrology and Hypertension Section Miami Veterans Affairs Medical Center (111C1), Miami, Florida; and
| | - Runxia Tian
- Nephrology and Hypertension Section Miami Veterans Affairs Medical Center (111C1), Miami, Florida; and
| | - Jenny S Wong
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - John C He
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kirk N Campbell
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York
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Ha TS, Hong EJ, Han GD. Diabetic conditions downregulate the expression of CD2AP in podocytes via PI3-K/Akt signalling. Diabetes Metab Res Rev 2015; 31:50-60. [PMID: 24846128 DOI: 10.1002/dmrr.2562] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 07/23/2012] [Accepted: 09/10/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND Proteinuria is typically accompanied by structural and compositional changes of the foot processes and of the slit diaphragms between podocytes. CD2-associated protein (CD2AP) in podocytes serves as an adaptor protein binding to nephrin and podocin, anchoring these slit diaphragm proteins to actin filaments of podocyte cytoskeleton and sending signals inward or outward. METHODS In the present study, we prepared streptozotocin-induced diabetic renal tissues and cultured podocytes in diabetic conditions to investigate podocyte phenotypical changes, including quantitative and distributional changes of CD2AP protein and search for the signalling mechanisms in diabetic conditions. We prepared cultured rat glomerular epithelial cells and mouse podocytes to study how high glucose and advanced glycosylation end products (AGE) induce phenotypical changes of cultured podocyte, under (1) normal glucose (5 mM, = control), (2) high glucose (30 mM), (3) AGE-added or (4) high glucose plus AGE-added conditions. RESULTS According to diabetic duration, density of CD2AP in renal tissue of experimental diabetic nephropathy became conglomerulated and diminished. In cultured podocytes, CD2AP co-localized with nephrin and zonula occludens-1 by confocal imaging. High glucose and high glucose plus AGE induced the relocalization and concentration of CD2AP at internal cytoplasmic and perinuclear areas of podocytes. High glucose plus AGE-added condition also decreased CD2AP protein amount and its mRNA expression compared with normal glucose or osmotic control conditions. In addition, LY294002, a phosphoinositide 3-kinase inhibitor, prevented the quantitative and distributional changes of CD2AP induced by high glucose and AGE. CONCLUSIONS These findings suggest that diabetic conditions induce the phenotypical changes of podocyte CD2AP possibly via phosphoinositide 3-kinase/Akt signalling.
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Affiliation(s)
- Tae-Sun Ha
- Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, Korea
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Dexamethasone inhibits podocyte apoptosis by stabilizing the PI3K/Akt signal pathway. BIOMED RESEARCH INTERNATIONAL 2013; 2013:326986. [PMID: 23710442 PMCID: PMC3655450 DOI: 10.1155/2013/326986] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Revised: 03/16/2013] [Accepted: 03/28/2013] [Indexed: 02/01/2023]
Abstract
Corticosteroids like dexamethasone (DEX) are well-established treatments for the glomerular disease that sustain renal function, at least in part, by protecting podocytes from apoptotic death. In this study, we found that PAN causes abnormal expression of the PI3K-binding protein CD2AP, reducing PI3K/Akt signaling and promoting podocyte apoptosis. In contrast, DEX restores CD2AP-PI3K-Akt-GSK3 β signaling, which promotes the activity of antiapoptotic proteins and inhibits the activity of proapoptotic proteins. In addition, we also found that CD2AP was aberrantly colocalized with p85. Normal CD2AP mRNA expression and subcellular protein distribution were maintained in the PAN + DEX group, and DEX coapplication also reduced CD2AP-p85 colocalization. PAN evoked a concentration-dependent decrease in p-Akt and p-GSK3 β expressions, with p-Akt expression reaching a nadir at 15 min and p-GSK3 β expression at 30 min. DEX treatment induced a concentration-dependent reversal of PAN-induced p-Akt and p-GSK3 β downregulation. The PI3K inhibitor LY294002 blocked p-Akt and p-GSK3 β expressions in podocytes. Cells treated with PAN exhibited a significantly higher apoptosis rate than untreated or vehicle-treated cells. Furthermore, LY294002 exacerbated PAN-induced apoptosis. DEX cotreatment caused a significant concentration-dependent decrease in PAN-induced apoptosis. These results strongly suggest that DEX protects podocytes by stabilizing the expression and subcellular distribution of CD2AP and by maintaining the expression of phosphor-activated Akt and GSK3β .
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Ha TS. Roles of adaptor proteins in podocyte biology. World J Nephrol 2013; 2:1-10. [PMID: 24175259 PMCID: PMC3782205 DOI: 10.5527/wjn.v2.i1.1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 10/26/2012] [Accepted: 01/06/2013] [Indexed: 02/06/2023] Open
Abstract
Podocytes covering the glomerular basement membrane over the glomerular capillary consist of three morphologically and functionally different segments, the cell body, major processes and extending finger-like foot processes (FPs). The FPs of neighboring podocytes are connected by a continuous adherent junction structure named the slit diaphragm (SD). The extracellular SD is linked to the intracellular, a highly dynamic, cytoskeleton through adaptor proteins. These adaptor proteins, such as CD2-associated protein, zonula occludens 1, β-catenin, Nck and p130Cas, located at the intracellular SD insertion area near lipid rafts, have important structural and functional roles. Adaptor proteins in podocytes play important roles as a structural component of the podocyte structure, linking the SD to the cytoskeletal structure and as a signaling platform sending signals from the SD to the actin cytoskeleton. This review discusses the roles of adaptor proteins in the podocyte cytoskeletal structure and signaling from the SD to the actin cytoskeleton.
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Lu H, Kapur G, Mattoo TK, Lyman WD. Hypoxia decreases podocyte expression of slit diaphragm proteins. Int J Nephrol Renovasc Dis 2012; 5:101-7. [PMID: 22888268 PMCID: PMC3413038 DOI: 10.2147/ijnrd.s27332] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Chronic hypoxia contributes to progressive tubulointerstitial injury and, consequently, renal failure. However, the effect of hypoxia on glomerular podocytes, which are integral to the slit diaphragm complex and responsible for selectivity of the glomerular filtration barrier, has not been completely determined. Methods Conditionally immortalized mouse podocyte cells were exposed to hypoxic (1% O2) or normoxic (room air) conditions for 24, 48, or 72 hours, after which cell viability was determined by MTT assay. Cells were stained with podocin and phalloidin to determine podocin and intracellular actin distribution. Expression of synaptopodin, CD2-associated protein (CD2AP), NcK, transforming growth factor-β1 (TGF-β1), hypoxia-inducible factor (HIF-1α) were evaluated by real-time polymerase chain reaction. Results Podocytes exposed to hypoxia had significantly reduced viability at 48 (87%) and 72 hours (66%). There was disarrangement of intracellular filament actin by phalloidin staining, a 30% weaker fluorescence intensity by podocin staining, significantly reduced expression of synaptopodin (12%), CD2AP (42%), NcK (38%), and increased expression of TGF-β1 and P-ERK after hypoxia treatment. Conclusion Podocyte exposure to hypoxia leads to reduced viability and SD protein expression, which may explain persistent and/or increasing proteinuria in patients with progressive renal failure. Increased expression of TGF-β1 and P-ERK is associated with apoptosis and fibrosis, which could be the link between hypoxia and glomerular injury.
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Affiliation(s)
- Hong Lu
- Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA
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Schell C, Huber TB. New players in the pathogenesis of focal segmental glomerulosclerosis. Nephrol Dial Transplant 2012; 27:3406-12. [PMID: 22767631 DOI: 10.1093/ndt/gfs273] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Since the first description of this clinicopathological entity in the early 1930s, various studies have identified numerous underlying pathogenetic mechanisms. Nevertheless, FSGS is still a complex, only partially understood and in its classification sometimes confusing disease. A unifying pathophysiological concept has not been identified and might not even exist. However, research efforts of past decades identified FSGS as a podocytopathy with several podocyte molecules being key players in the development and the course of FSGS. Podocytes are crucially involved in the formation of the glomerular barrier and any assault on their delicate physiological balance and architecture can result in the development of proteinuria. The following review article will introduce most recent examples identifying novel players in the complex pathogenesis of FSGS.
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Yaddanapudi S, Altintas MM, Kistler AD, Fernandez I, Möller CC, Wei C, Peev V, Flesche JB, Forst AL, Li J, Patrakka J, Xiao Z, Grahammer F, Schiffer M, Lohmüller T, Reinheckel T, Gu C, Huber TB, Ju W, Bitzer M, Rastaldi MP, Ruiz P, Tryggvason K, Shaw AS, Faul C, Sever S, Reiser J. CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest 2011; 121:3965-80. [PMID: 21911934 DOI: 10.1172/jci58552] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2011] [Accepted: 07/20/2011] [Indexed: 12/11/2022] Open
Abstract
Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-β1-dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actin-associated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-β1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-β response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.
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Affiliation(s)
- Suma Yaddanapudi
- Nephrology Division, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA
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Herbach N, Schairer I, Blutke A, Kautz S, Siebert A, Göke B, Wolf E, Wanke R. Diabetic kidney lesions of GIPRdn transgenic mice: podocyte hypertrophy and thickening of the GBM precede glomerular hypertrophy and glomerulosclerosis. Am J Physiol Renal Physiol 2009; 296:F819-29. [DOI: 10.1152/ajprenal.90665.2008] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Diabetic nephropathy is the leading cause of end-stage renal disease and the largest contributor to the total cost of diabetes care. Rodent models are excellent tools to gain more insight into the pathogenesis of diabetic nephropathy. In the present study, we characterize the age-related sequence of diabetes-associated kidney lesions in GIPRdn transgenic mice, a novel mouse model of early-onset diabetes mellitus. Clinical-chemical analyses as well as qualitative and quantitative morphological analyses of the kidneys of GIPRdn transgenic animals and nontransgenic littermate controls were performed at 3, 8, 20, and 28 wk of age. Early renal changes of transgenic mice consisted of podocyte hypertrophy, reduced numerical volume density of podocytes in glomeruli, and homogenous thickening of the glomerular basement membrane, followed by renal and glomerular hypertrophy as well as mesangial expansion and matrix accumulation. At 28 wk of age, glomerular damage was most prominent, including advanced glomerulosclerosis, tubulointerstitial lesions, and proteinuria. Real-time PCR demonstrated increased glomerular expression of Col4a1, Fn1, and Tgfb1. Immunohistochemistry revealed increased mesangial deposition of collagen type IV, fibronectin, and laminin. The present study shows that GIPRdn transgenic mice exhibit renal changes that closely resemble diabetes-associated kidney alterations in humans. Data particularly from male transgenic mice indicate that podocyte hypertrophy is directly linked to hyperglycemia, without the influence of mechanical stress. GIPRdn transgenic mice are considered an excellent new tool to study the mechanisms involved in onset and progression of diabetic nephropathy.
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Abstract
Kidney tissue laser capture microdissection (LCM) is of great clinical relevance since genome wide studies on total kidney messenger RNA (mRNA) potentially miss important factors involved in the pathogenesis of the disease in glomeruli and tubules. This technique is readily applicable to study mRNA from isolated glomeruli and tubules of human kidney biopsy material. In this chapter we present a "cook-book" practical approach of utilizing LCM in combination with RNA isolation technique in downstream applications in nephrology.
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Johnson RI, Seppa MJ, Cagan RL. The Drosophila CD2AP/CIN85 orthologue Cindr regulates junctions and cytoskeleton dynamics during tissue patterning. ACTA ACUST UNITED AC 2008; 180:1191-204. [PMID: 18362180 PMCID: PMC2290846 DOI: 10.1083/jcb.200706108] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Developing tissues require cells to undergo intricate processes to shift into appropriate niches. This requires a functional connection between adhesion-mediating events at the cell surface and a cytoskeletal reorganization to permit directed movement. A small number of proteins are proposed to link these processes. Here, we identify one candidate, Cindr, the sole Drosophila melanogaster member of the CD2AP/CIN85 family (this family has been previously implicated in a variety of processes). Using D. melanogaster retina, we demonstrate that Cindr links cell surface junctions (E-cadherin) and adhesion (Roughest) with multiple components of the actin cytoskeleton. Reducing cindr activity leads to defects in local cell movement and, consequently, tissue patterning and cell death. Cindr activity is required for normal localization of Drosophila E-cadherin and Roughest, and we show additional physical and functional links to multiple components of the actin cytoskeleton, including the actin-capping proteins capping protein alpha and capping protein beta. Together, these data demonstrate that Cindr is involved in dynamic cell rearrangement in an emerging epithelium.
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Affiliation(s)
- Ruth I Johnson
- Department of Developmental and Regenerative Biology, Mount Sinai Medical School, New York, NY 10029, USA
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