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Khare V, Cherqui S. Targeted gene therapy for rare genetic kidney diseases. Kidney Int 2024; 106:1051-1061. [PMID: 39222842 DOI: 10.1016/j.kint.2024.07.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/13/2024] [Accepted: 07/01/2024] [Indexed: 09/04/2024]
Abstract
Chronic kidney disease is one of the leading causes of mortality worldwide because of kidney failure and the associated challenges of its treatment including dialysis and kidney transplantation. About one-third of chronic kidney disease cases are linked to inherited monogenic factors, making them suitable for potential gene therapy interventions. However, the intricate anatomical structure of the kidney poses a challenge, limiting the effectiveness of targeted gene delivery to the renal system. In this review, we explore the progress made in the field of targeted gene therapy approaches and their implications for rare genetic kidney disorders, examining preclinical studies and prospects for clinical application. In vivo gene therapy is most commonly used for kidney-targeted gene delivery and involves administering viral and nonviral vectors through various routes such as systemic, renal vein, and renal arterial injections. Small nucleic acids have also been used in preclinical and clinical studies for treating certain kidney disorders. Unexpectedly, hematopoietic stem and progenitor cells have been used as an ex vivo gene therapy vehicle for kidney gene delivery, highlighting their ability to differentiate into macrophages within the kidney, forming tunneling nanotubes that can deliver genetic material and organelles to adjacent kidney cells, even across the basement membrane to target the proximal tubular cells. As gene therapy technologies continue to advance and our understanding of kidney biology deepens, there is hope for patients with genetic kidney disorders to eventually avoid kidney transplantation.
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Affiliation(s)
- Veenita Khare
- Department of Pediatrics, Division of Genetics, University of California, San Diego, La Jolla, California, USA
| | - Stephanie Cherqui
- Department of Pediatrics, Division of Genetics, University of California, San Diego, La Jolla, California, USA.
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2
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Oda K, Katayama K, Zang L, Toda M, Tanoue A, Saiki R, Yasuma T, D’Alessandro-Gabazza CN, Shimada Y, Mori M, Suzuki Y, Murata T, Hirai T, Tryggvason K, Gabazza EC, Dohi K. The Protective Role of KANK1 in Podocyte Injury. Int J Mol Sci 2024; 25:5808. [PMID: 38891998 PMCID: PMC11172089 DOI: 10.3390/ijms25115808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/21/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
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Affiliation(s)
- Keiko Oda
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
| | - Kan Katayama
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
| | - Liqing Zang
- Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507, Mie, Japan;
| | - Masaaki Toda
- Department of Immunology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (M.T.); (T.Y.); (C.N.D.-G.); (E.C.G.)
| | - Akiko Tanoue
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
| | - Ryosuke Saiki
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
| | - Taro Yasuma
- Department of Immunology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (M.T.); (T.Y.); (C.N.D.-G.); (E.C.G.)
| | - Corina N. D’Alessandro-Gabazza
- Department of Immunology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (M.T.); (T.Y.); (C.N.D.-G.); (E.C.G.)
| | - Yasuhito Shimada
- Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan;
| | - Mutsuki Mori
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
| | - Yasuo Suzuki
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
| | - Tomohiro Murata
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
| | - Toshinori Hirai
- Department of Pharmacy, Faculty of Medicine, Mie University Hospital, Tsu 514-8507, Mie, Japan;
| | - Karl Tryggvason
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden;
| | - Esteban C. Gabazza
- Department of Immunology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (M.T.); (T.Y.); (C.N.D.-G.); (E.C.G.)
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (K.O.); (A.T.); (R.S.); (M.M.); (Y.S.); (T.M.); (K.D.)
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Peek JL, Wilson MH. Cell and gene therapy for kidney disease. Nat Rev Nephrol 2023:10.1038/s41581-023-00702-3. [PMID: 36973494 DOI: 10.1038/s41581-023-00702-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2023] [Indexed: 03/29/2023]
Abstract
Kidney disease is a leading cause of morbidity and mortality across the globe. Current interventions for kidney disease include dialysis and renal transplantation, which have limited efficacy or availability and are often associated with complications such as cardiovascular disease and immunosuppression. There is therefore a pressing need for novel therapies for kidney disease. Notably, as many as 30% of kidney disease cases are caused by monogenic disease and are thus potentially amenable to genetic medicine, such as cell and gene therapy. Systemic disease that affects the kidney, such as diabetes and hypertension, might also be targetable by cell and gene therapy. However, although there are now several approved gene and cell therapies for inherited diseases that affect other organs, none targets the kidney. Promising recent advances in cell and gene therapy have been made, including in the kidney research field, suggesting that this form of therapy might represent a potential solution for kidney disease in the future. In this Review, we describe the potential for cell and gene therapy in treating kidney disease, focusing on recent genetic studies, key advances and emerging technologies, and we describe several crucial considerations for renal genetic and cell therapies.
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Affiliation(s)
- Jennifer L Peek
- Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Matthew H Wilson
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Veterans Affairs, Tennessee Valley Health Services, Nashville, TN, USA.
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Tanoue A, Katayama K, Ito Y, Joh K, Toda M, Yasuma T, D'Alessandro-Gabazza CN, Kawachi H, Yan K, Ito M, Gabazza EC, Tryggvason K, Dohi K. Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis. Sci Rep 2021; 11:20556. [PMID: 34654837 PMCID: PMC8519956 DOI: 10.1038/s41598-021-00159-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/07/2021] [Indexed: 11/15/2022] Open
Abstract
Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patients with steroid-resistant nephrotic syndrome, although the precise mechanism is unclear. The present study demonstrated that podocyte-specific Crb2 knockout mice develop massive albuminuria and microhematuria 2-month after birth and focal segmental glomerulosclerosis and tubulointerstitial fibrosis with hemosiderin-laden macrophages at 6-month of age. Transmission and scanning electron microscopic studies demonstrated injury and foot process effacement of podocytes in 6-month aged podocyte-specific Crb2 knockout mice. The number of glomerular Wt1-positive cells and the expressions of Nphs2, Podxl, and Nphs1 were reduced in podocyte-specific Crb2 knockout mice compared to negative control mice. Human podocytes lacking CRB2 had significantly decreased F-actin positive area and were more susceptible to apoptosis than their wild-type counterparts. Overall, this study's results suggest that the specific deprivation of Crb2 in podocytes induces altered actin cytoskeleton reorganization associated with dysfunction and accelerated apoptosis of podocytes that ultimately cause focal segmental glomerulosclerosis.
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Affiliation(s)
- Akiko Tanoue
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Kan Katayama
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
| | - Yugo Ito
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Kensuke Joh
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masaaki Toda
- Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan
| | - Taro Yasuma
- Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan
| | | | - Hiroshi Kawachi
- Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kunimasa Yan
- Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Esteban C Gabazza
- Department of Immunology, Mie University Graduate School of Medicine, Mie, Japan
| | - Karl Tryggvason
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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Abstract
The number of individuals affected by acute kidney injury (AKI) and chronic kidney disease (CKD) is constantly rising. In light of the limited availability of treatment options and their relative inefficacy, cell based therapeutic modalities have been studied. However, not many efforts are put into safety evaluation of such applications. The aim of this study was to review the existing published literature on adverse events reported in studies with genetically modified cells for treatment of kidney disease. A systematic review was conducted by searching PubMed and EMBASE for relevant articles published until June 2018. The search results were screened and relevant articles selected using pre-defined criteria, by two researchers independently. After initial screening of 6894 abstracts, a total number of 97 preclinical studies was finally included for full assessment. Of these, 61 (63%) presented an inappropriate study design for the evaluation of safety parameters. Only 4 studies (4%) had the optimal study design, while 32 (33%) showed sub-optimal study design with either direct or indirect evidence of adverse events. The high heterogeneity of studies included regarding cell type and number, genetic modification, administration route, and kidney disease model applied, combined with the consistent lack of appropriate control groups, makes a reliable safety evaluation of kidney cell-based therapies impossible. Only a limited number of relevant studies included looked into essential safety-related outcomes, such as inflammatory (48%), tumorigenic and teratogenic potential (12%), cell biodistribution (82%), microbiological safety with respect to microorganism contamination and latent viruses' reactivation (1%), as well as overall well-being and animal survival (19%). In conclusion, for benign cell-based therapies, well-designed pre-clinical studies, including all control groups required and good manufacturing processes securing safety, need to be done early in development. Preferably, this should be performed side by side with efficacy evaluation and according to the official guidelines of leading health organizations.
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Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome. Kidney Int 2017; 91:1347-1361. [DOI: 10.1016/j.kint.2016.12.022] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 12/20/2016] [Accepted: 12/22/2016] [Indexed: 01/11/2023]
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Nyström A, Bornert O, Kühl T. Cell therapy for basement membrane-linked diseases. Matrix Biol 2016; 57-58:124-139. [PMID: 27609402 DOI: 10.1016/j.matbio.2016.07.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 06/02/2016] [Accepted: 07/07/2016] [Indexed: 12/14/2022]
Abstract
For most disorders caused by mutations in genes encoding basement membrane (BM) proteins, there are at present only limited treatment options available. Genetic BM-linked disorders can be viewed as especially suited for treatment with cell-based therapy approaches because the proteins that need to be restored are located in the extracellular space. In consequence, complete and permanent engraftment of cells does not necessarily have to occur to achieve substantial causal therapeutic effects. For these disorders cells can be used as transient vehicles for protein replacement. In addition, it is becoming evident that BM-linked genetic disorders are modified by secondary diseases mechanisms. Cell-based therapies have also the ability to target such disease modifying mechanisms. Thus, cell therapies can simultaneously provide causal treatment and symptomatic relief, and accordingly hold great potential for treatment of BM-linked disorders. However, this potential has for most applications and diseases so far not been realized. Here, we will present the state of cell therapies for BM-linked diseases. We will discuss use of both pluripotent and differentiated cells, the limitation of the approaches, their challenges, and the way forward to potential wider implementation of cell therapies in the clinics.
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Affiliation(s)
- Alexander Nyström
- Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
| | - Olivier Bornert
- Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany
| | - Tobias Kühl
- Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany
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8
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COL4A6 is dispensable for autosomal recessive Alport syndrome. Sci Rep 2016; 6:29450. [PMID: 27377778 PMCID: PMC4932521 DOI: 10.1038/srep29450] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/17/2016] [Indexed: 01/27/2023] Open
Abstract
Alport syndrome is caused by mutations in the genes encoding α3, α4, or α5 (IV) chains. Unlike X-linked Alport mice, α5 and α6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both α3 and α6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 × 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 × 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The α5 and α6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although α5 and α6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.
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9
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Savva I, Pierides A, Deltas C. RAAS inhibition and the course of Alport syndrome. Pharmacol Res 2016; 107:205-210. [PMID: 26995302 DOI: 10.1016/j.phrs.2016.03.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 03/04/2016] [Accepted: 03/14/2016] [Indexed: 12/26/2022]
Abstract
Alport syndrome (AS) is a hereditary progressive glomerulonephritis with a high life-time risk for end-stage renal disease (ESRD). Most patients will reach ESRD before the age of 30 years, while a subset of them with milder mutations will do so at older ages, even after 50 years. Frequent extrarenal manifestations are hearing loss and ocular abnormalities. AS is a genetically heterogeneous collagen IV nephropathy, with 85% of the cases caused by mutations in the X-linked COL4A5 gene and the rest by homozygous or compound heterozygous mutations in either the COL4A3 or the COL4A4 gene on chromosome 2q36-37. There is no radical cure for the disease and attempts to use various stem cell therapies in animal models have been met with ambiguous success. However, effective treatment has been accomplished with pharmacological intervention at the renin-angiotensin-aldosterone system (RAAS), first in animal models of AS and more recently in humans. Angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) have been shown to significantly delay the progression of chronic kidney disease and the onset of ESRD. Also, renin inhibitors and aldosterone blockade were used with positive results, while the combination of ACEis and ARBs was met with mixed success. An important study, the EARLY-PROTECT, aims at evaluating the efficacy of ACEis when administered very early on in children with AS. Novel therapies are also tested experimentally or are under design in animal models by several groups, including the use of amniotic fluid stem cells and synthetic chaperones.
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Affiliation(s)
- Isavella Savva
- Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Cyprus
| | - Alkis Pierides
- Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Cyprus; Department of Nephrology, Hippocrateon Hospital, Nicosia, Cyprus
| | - Constantinos Deltas
- Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Cyprus.
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Katayama K, Nomura S, Tryggvason K, Ito M. Searching for a treatment for Alport syndrome using mouse models. World J Nephrol 2014; 3:230-236. [PMID: 25374816 PMCID: PMC4220355 DOI: 10.5527/wjn.v3.i4.230] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 07/15/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Alport syndrome (AS) is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encoding the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identified and the first Alport mouse model was developed using a knockout approach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the pathogenesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharmacological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refinement as research advances. In terms of the pharmacological drugs, angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.
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Savige J. Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment. J Physiol 2014; 592:4013-23. [PMID: 25107927 DOI: 10.1113/jphysiol.2014.274449] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The glomerular filtration barrier comprises a fenestrated capillary endothelium, glomerular basement membrane and podocyte slit diaphragm. Over the past decade we have come to realise that permselectivity depends on size and not necessarily charge, that the molecular sieve depends on the podocyte contractile apparatus and is highly dynamic, and that protein uptake by proximal tubular epithelial cells stimulates signalling and the production of transcription factors and inflammatory mediators. Alport syndrome is the second commonest monogenic cause of renal failure after autosomal dominant polycystic kidney disease. Eighty per cent of patients have X-linked disease caused by mutations in the COL4A5 gene. Most of these result in the replacement of the collagen IV α3α4α5 network with the α1α1α2 heterotrimer. Affected membranes also have ectopic laminin and increased matrix metalloproteinase levels, which makes them more susceptible to proteolysis. Mechanical stress, due to the less elastic membrane and hypertension, interferes with integrin-mediated podocyte-GBM adhesion. Proteinuria occurs when urinary levels exceed tubular reabsorption rates, and initiates tubulointerstitial fibrosis. The glomerular mesangial cells produce increased TGFβ and CTGF which also contribute to glomerulosclerosis. Currently there is no specific therapy for Alport syndrome. However treatment with angiotensin converting enzyme (ACE) inhibitors delays renal failure progression by reducing intraglomerular hypertension, proteinuria, and fibrosis. Our greater understanding of the mechanisms underlying the GBM changes and their consequences in Alport syndrome have provided us with further novel therapeutic targets.
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Affiliation(s)
- Judy Savige
- University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia
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12
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13
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Lin X, Suh JH, Go G, Miner JH. Feasibility of repairing glomerular basement membrane defects in Alport syndrome. J Am Soc Nephrol 2013; 25:687-92. [PMID: 24262794 DOI: 10.1681/asn.2013070798] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Alport syndrome is a hereditary glomerular disease that leads to kidney failure. It is caused by mutations affecting one of three chains of the collagen α3α4α5(IV) heterotrimer, which forms the major collagen IV network of the glomerular basement membrane (GBM). In the absence of the α3α4α5(IV) network, the α1α1α2(IV) network substitutes, but it is insufficient to maintain normal kidney function. Inhibition of angiotensin-converting enzyme slows progression to kidney failure in patients with Alport syndrome but is not a cure. Restoration of the normal collagen α3α4α5(IV) network in the GBM, by either cell- or gene-based therapy, is an attractive and logical approach toward a cure, but whether or not the abnormal GBM can be repaired once it has formed and is functioning is unknown. Using a mouse model of Alport syndrome and an inducible transgene system, we found that secretion of α3α4α5(IV) heterotrimers by podocytes into a preformed, abnormal, filtering Alport GBM is effective at restoring the missing collagen IV network, slowing kidney disease progression, and extending life span. This proof-of-principle study demonstrates the plasticity of the mature GBM and validates the pursuit of therapeutic approaches aimed at normalizing the GBM to prolong kidney function.
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14
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An update on the pathomechanisms and future therapies of Alport syndrome. Pediatr Nephrol 2013; 28:1025-36. [PMID: 22903660 DOI: 10.1007/s00467-012-2272-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 07/12/2012] [Accepted: 07/13/2012] [Indexed: 01/08/2023]
Abstract
Alport Syndrome (AS) is an inherited progressive disease that is caused by mutations of the genes encoding the key collagen chains, α3, α4, and α5, which are necessary for the composition of collagen type IV to form a robust glomerular basement membrane (GBM), capable of withstanding the significant biomechanical strain to which the glomerulus is subjected. Progressive loss of the filtration barrier allows excessive proteinuria, which ultimately leads to end-stage kidney disease (ESKD). The evidence for a beneficial renoprotective effect of renin-angiotensin-aldosterone system (RAAS) blockade by angiotensin-converting enzyme (ACE) inhibition and/or angiotensin receptor blockers (ARBs) is well established in AS and recent evidence has shown that it can significantly delay the time to onset of renal replacement therapy and ESKD. Future potential treatments of AS disease progression are evaluated in this review.
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15
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Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelmann B, Rheault M, Licht C. Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol 2013; 28:5-11. [PMID: 22461141 PMCID: PMC3505543 DOI: 10.1007/s00467-012-2138-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 01/29/2012] [Accepted: 01/31/2012] [Indexed: 12/21/2022]
Abstract
We present clinical practice recommendations for the treatment of children with Alport syndrome who are not enrolled in clinical trials. Our goal is to promote early initiation of a standard therapeutic approach that will facilitate assessment of the safety and efficacy of the protocol. The treatment protocol is based on the reduction of proteinuria, intraglomerular pressure, and renal fibrosis via interference with the renin-angiotensin-aldosterone system.
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Affiliation(s)
- Clifford E. Kashtan
- Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Medical School, Minneapolis, MN USA
| | - Jie Ding
- Pediatric Department, Peking University First Hospital, Beijing, People’s Republic of China
| | - Martin Gregory
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT USA
| | - Oliver Gross
- Department of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
| | - Laurence Heidet
- Centre de référence pour les Maladies Rénales Héréditaires de l’Enfant et de l’Adulte (MARHEA) and Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants malades, Paris, France
| | - Bertrand Knebelmann
- Centre de référence pour les Maladies Rénales Héréditaires de l’Enfant et de l’Adulte (MARHEA) and Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants malades, Paris, France
| | - Michelle Rheault
- Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Medical School, Minneapolis, MN USA
| | - Christoph Licht
- The Hospital for Sick Children, Division of Nephrology, Toronto, Canada
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Kruegel J, Rubel D, Gross O. Alport syndrome--insights from basic and clinical research. Nat Rev Nephrol 2012; 9:170-8. [PMID: 23165304 DOI: 10.1038/nrneph.2012.259] [Citation(s) in RCA: 175] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In this Review, we discuss the latest basic and clinical research on Alport syndrome, focusing on the roles of podocyte pathology and the extracellular matrix. We also highlight early diagnosis and treatment options for young patients with this disorder.
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Affiliation(s)
- Jenny Kruegel
- Department of Nephrology and Rheumatology, University Medicine Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany
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17
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Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr Nephrol 2012; 27:885-90. [PMID: 21455721 PMCID: PMC3484979 DOI: 10.1007/s00467-011-1868-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 03/09/2011] [Accepted: 03/10/2011] [Indexed: 01/28/2023]
Abstract
We have known for some time that mutations in the genes encoding 3 of the 6 type IV collagen chains are the underlying defect responsible for both X-linked (where the COL4A5 gene is involved) and autosomal (where either COL4A3 or COL4A4 genes are involved) Alport syndrome. The result of these mutations is the absence of the sub-epithelial network of all three chains in the glomerular basement membrane (GBM), resulting, at maturity, in a type IV collagen GBM network comprising only α1(IV) and α2(IV) chains. The altered GBM functions adequately in early life. Eventually, there is onset of proteinuria associated with the classic and progressive irregular thickening, thinning, and splitting of the GBM, which culminates in end-stage renal failure. We have learned much about the molecular events associated with disease onset and progression through the study of animal models for Alport syndrome, and have identified some potential therapeutic approaches that may serve to delay the onset or slow the progression of the disease. This review focuses on where we are in our understanding of the disease, where we need to go to understand the molecular triggers that set the process in motion, and what emergent therapeutic approaches show promise for ameliorating disease progression in the clinic.
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Abstract
Much attention recently has been focused on stem cell technology as a possible alternative modality of treatment of a variety of diseases. Chronic kidney disease is a serious health problem and most chronic kidney diseases share in common the presence of interstitial and glomerular fibrosis, regardless of the underlying cause. To date there are no specific therapies aimed at treating fibrosis in the kidney. In a novel effort to address the underlying pathology in kidney disease, researchers are demonstrating that stem cell therapy can attenuate fibrosis in chronic kidney disease in animal models. This review will focus on the recent developments in stem cell research and their possible implications to treat chronic kidney disease.
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Sedrakyan S, Da Sacco S, Milanesi A, Shiri L, Petrosyan A, Varimezova R, Warburton D, Lemley KV, De Filippo RE, Perin L. Injection of amniotic fluid stem cells delays progression of renal fibrosis. J Am Soc Nephrol 2012; 23:661-73. [PMID: 22302195 DOI: 10.1681/asn.2011030243] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Injection of amniotic fluid stem cells ameliorates the acute phase of acute tubular necrosis in animals by promoting proliferation of injured tubular cells and decreasing apoptosis, but whether these stem cells could be of benefit in CKD is unknown. Here, we used a mouse model of Alport syndrome, Col4a5(-/-) mice, to determine whether amniotic fluid stem cells could modify the course of progressive renal fibrosis. Intracardiac administration of amniotic fluid stem cells before the onset of proteinuria delayed interstitial fibrosis and progression of glomerular sclerosis, prolonged animal survival, and ameliorated the decline in kidney function. Treated animals exhibited decreased recruitment and activation of M1-type macrophages and a higher proportion of M2-type macrophages, which promote tissue remodeling. Amniotic fluid stem cells did not differentiate into podocyte-like cells and did not stimulate production of the collagen IVa5 needed for normal formation and function of the glomerular basement membrane. Instead, the mechanism of renal protection was probably the paracrine/endocrine modulation of both profibrotic cytokine expression and recruitment of macrophages to the interstitial space. Furthermore, injected mice retained a normal number of podocytes and had better integrity of the glomerular basement membrane compared with untreated Col4a5(-/-) mice. Inhibition of the renin-angiotensin system by amniotic fluid stem cells may contribute to these beneficial effects. In conclusion, treatment with amniotic fluid stem cells may be beneficial in kidney diseases characterized by progressive renal fibrosis.
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Affiliation(s)
- Sargis Sedrakyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California 90027, USA
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20
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Kidney repair and stem cells: a complex and controversial process. Pediatr Nephrol 2011; 26:1427-34. [PMID: 21336814 DOI: 10.1007/s00467-011-1789-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 01/17/2011] [Accepted: 01/24/2011] [Indexed: 02/06/2023]
Abstract
Over the last decade, stem cells have been the topic of much debate and investigation for their regenerative potential in the case of renal injury. This review focuses on bone marrow stem cells (BMSC) for renal repair and the potential origins of the controversial results between studies. Some authors have shown that BMSC can differentiate into renal cells and reverse renal dysfunction while others obtained contradictory results. One significant variation between these studies is the choice of BMSC used. According to the literature and our own experience, unfractionated bone marrow cells and hematopoietic stem cells are able to lead to long-term cell tissue engraftment and repair, whereas mesenchymal stem cells have a short-term paracrine effect. Detection of the bone-marrow-derived cells is also an important source of error. However, the major difference between studies is the model of kidney injury used. Two categories of models have to be distinguished: acute and chronic kidney disease. However, variation within these categories also exists. The outcomes of various strategies for BMSC transplantation after injury to the kidney must be compared within a single model and cannot be transposed from one model to another.
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21
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Kunter U, Rong S, Moeller MJ, Floege J. Mesenchymal stem cells as a therapeutic approach to glomerular diseases: benefits and risks. Kidney Int Suppl (2011) 2011; 1:68-73. [PMID: 25018904 PMCID: PMC4089694 DOI: 10.1038/kisup.2011.16] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Most studies using adult stem cells (ASCs) and progenitor cells as potential therapeutics for kidney disorders have been conducted in models of acute kidney injury, where the damage mainly affects the tubulointerstitium. The results are promising, whereas the underlying mechanisms are still being discussed controversially. Glomerular diseases have not received as much attention. Likely reasons include the often insidious onset, rendering the choice of optimal treatment timing difficult, and the fact that chronic diseases may require long-term therapy. In this mini review, we summarize current strategies in adult stem cell-based therapies for glomerular diseases. In addition, we focus on possible side effects of stem cell administration that have been reported recently, that is, profibrotic actions and maldifferentiation of mesenchymal stem cells.
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Affiliation(s)
- Uta Kunter
- Department of Nephrology and Immunology, Medical Faculty, RWTH University of Aachen , Aachen, Germany
| | - Song Rong
- Department of Nephrology and Immunology, Medical Faculty, RWTH University of Aachen , Aachen, Germany
| | - Marcus J Moeller
- Department of Nephrology and Immunology, Medical Faculty, RWTH University of Aachen , Aachen, Germany
| | - Jürgen Floege
- Department of Nephrology and Immunology, Medical Faculty, RWTH University of Aachen , Aachen, Germany
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22
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Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-α-mediated podocyte loss. Kidney Int 2011; 79:189-98. [DOI: 10.1038/ki.2010.373] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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23
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24
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Nagy A, Quaggin SE. Stem Cell Therapy for the Kidney: A Cautionary Tale. J Am Soc Nephrol 2010; 21:1070-2. [DOI: 10.1681/asn.2010050559] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Huls M, Schoeber JPH, Verfaillie CM, Luttun A, Ulloa-Montoya F, Menke AL, van Bolderen LR, Woestenenk RM, Merkx GFM, Wetzels JFM, Russel FGM, Masereeuw R. Deficiency of either P-glycoprotein or breast cancer resistance protein protect against acute kidney injury. Cell Transplant 2010; 19:1195-208. [PMID: 20977831 DOI: 10.3727/096368910x504478] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The kidney has a high capacity to regenerate after ischemic injury via several mechanisms, one of which involves bone marrow-derived (stem) cells. The ATP binding cassette transporters, P-glycoprotein and breast cancer resistance protein, are determinants for the enriched stem and progenitor cell fraction in bone marrow. Because they are upregulated after acute kidney injury, we hypothesized that both efflux pumps may play a role in protecting against renal injury. Surprisingly, transporter-deficient mice were protected against ischemia-induced renal injury. To further study this, bone marrow from irradiated wild-type mice was reconstituted by bone marrow from wild-type, P-glycoprotein- or breast cancer resistance protein-deficient mice. Four weeks later, kidney injury was induced and its function evaluated. Significantly more bone marrow-derived cells were detected in kidneys grafted with transporter-deficient bone marrow. A gender mismatch study suggested that cell fusion of resident tubular cells with bone marrow cells was unlikely. Renal function analyses indicated an absence of renal damage following ischemia-reperfusion in animals transplanted with transporter-deficient bone marrow. When wild-type bone marrow was transplanted in breast cancer resistance protein-deficient mice this protection is lost. Furthermore, we demonstrate that transporter-deficient bone marrow contained significantly more monocytes, granulocytes, and early outgrowth endothelial progenitor cells.
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Affiliation(s)
- Miriam Huls
- Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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26
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Terryn S, Devuyst O, Antignac C. Cell therapy for cystinosis. Nephrol Dial Transplant 2010; 25:2103-6. [PMID: 20395258 DOI: 10.1093/ndt/gfq198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In the September 2009 issue of Blood, Syres et al. [1] report on syngeneic bone marrow cell (BMC) and haematopoietic stem cell (HSC) therapy as a successful treatment in a mouse model of cystinosis, an autosomal recessive metabolic disease caused by a defect in the transport of cystine across the lysosomal membrane. The accumulation of cystine crystals in lysosomes leads to a multi-organ dysfunction including proximal tubulopathy and renal failure, corneal deposits, myopathy and central nervous system defects. By using Ctns knock-out (Ctns(-/-)) mice as a model for cystinosis, Syres et al. show that BMC transplantation leads to a major reduction of cystine content in all tissues tested, reflected by a significant attenuation of the development and progression of kidney injury and reduction in the number of mice with corneal cystine crystals. These changes were correlated with the engraftment of donor BMC producing a functional cystine transporter in the tissues tested. The transplantation of mouse HSC had the same therapeutic effect than whole BMC in this model, which is important as such HSC can readily be isolated from peripheral blood in humans. This work suggests that BMC or HSC transplantation is a potential treatment for cystinosis and other renal tubular disorders.
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Affiliation(s)
- Sara Terryn
- Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels, Belgium
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27
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Tanaka M, Asada M, Higashi AY, Nakamura J, Oguchi A, Tomita M, Yamada S, Asada N, Takase M, Okuda T, Kawachi H, Economides AN, Robertson E, Takahashi S, Sakurai T, Goldschmeding R, Muso E, Fukatsu A, Kita T, Yanagita M. Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. J Clin Invest 2010; 120:768-77. [PMID: 20197625 DOI: 10.1172/jci39569] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.
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Affiliation(s)
- Mari Tanaka
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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28
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Little MH, Rae FK. Review article: Potential cellular therapies for renal disease: can we translate results from animal studies to the human condition? Nephrology (Carlton) 2009. [PMID: 19712255 DOI: 10.1111/j.1440-1797.2009.01144.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The incidence of chronic kidney disease is increasing worldwide, prompting considerable research into potential regenerative therapies. These have included studies to determine whether an endogenous renal stem cell exists in the postnatal kidney and whether non-renal adult stem cells, such as mesenchymal stem cell, can ameliorate renal damage. Such stem cells will either need to be recruited to the damaged kidney to repair the damage in situ or be differentiated into the desired cell type and delivered into the damaged kidney to subsequently elicit repair without maldifferentiation. To date, these studies have largely been performed using experimental and genetic models of renal damage in rodents. The translation of such research into a therapy applicable to human disease faces many challenges. In this review, we examine which animal models have been used to evaluate potential cellular therapies and how valid these are to human chronic kidney disease.
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Affiliation(s)
- Melissa H Little
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
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29
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Reinders MEJ, Fibbe WE, Rabelink TJ. Multipotent mesenchymal stromal cell therapy in renal disease and kidney transplantation. Nephrol Dial Transplant 2009; 25:17-24. [PMID: 19861311 DOI: 10.1093/ndt/gfp552] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cell therapies aim at differentiation of stem cells into the specific cell type required to repair damaged or destroyed cells or tissues. Over recent years, cell therapy has been introduced in a variety of application areas, including cardiovascular repair, diabetes, musculoskeletal disorders and renal repair. Multipotent mesenchymal stromal cells (MSCs), often referred to as mesenchymal stem cells, are of particular interest as a cell therapy model, as this is one of the few cell types that are on the brink of entering the clinical arena in different areas of application. MSCs can be differentiated in vitro and in vivo into various cell types of mesenchymal origin such as bone, fat and cartilage. They have important effects on the innate and adaptive immune system and possess striking anti-inflammatory properties that make them attractive for potential use in diseases characterized by autoimmunity and inflammation. In addition, MSCs have been shown to migrate to sites of tissue injury and to enhance repair by secreting anti-fibrotic and pro-angiogenic factors. In this review, evidence for the renoprotective mechanisms of MSCs as well as their therapeutic possibilities and potential hazards in acute and chronic renal disease and allograft rejection is summarized.
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LeBleu V, Sugimoto H, Mundel TM, Gerami-Naini B, Finan E, Miller CA, Gattone VH, Lu L, Shield CF, Folkman J, Kalluri R. Stem cell therapies benefit Alport syndrome. J Am Soc Nephrol 2009; 20:2359-70. [PMID: 19833902 DOI: 10.1681/asn.2009010123] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Patients with Alport syndrome progressively lose renal function as a result of defective type IV collagen in their glomerular basement membrane. In mice lacking the alpha3 chain of type IV collagen (Col4A3 knockout mice), a model for Alport syndrome, transplantation of wild-type bone marrow repairs the renal disease. It is unknown whether cell-based therapies that do not require transplantation have similar potential. Here, infusion of wild-type bone marrow-derived cells into unconditioned, nonirradiated Col4A3 knockout mice during the late stage of disease significantly improved renal histology and function. Furthermore, transfusion of unfractionated wild-type blood into unconditioned, nonirradiated Col4A3 knockout mice improved the renal phenotype and significantly improved survival. Injection of mouse and human embryonic stem cells into Col4A3 knockout mice produced similar results. Regardless of treatment modality, the improvement in the architecture of the glomerular basement membrane is associated with de novo expression of the alpha3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.
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Affiliation(s)
- Valerie LeBleu
- Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
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Abstract
In 1990, the role of basement membranes in human disease was established by the identification of COL4A5 mutations in Alport's syndrome. Since then, the number of diseases caused by mutations in basement membrane components has steadily increased as has our understanding of the roles of basement membranes in organ development and function. However, many questions remain as to the molecular and cellular consequences of these mutations and the way in which they lead to the observed disease phenotypes. Despite this, exciting progress has recently been made with potential treatment options for some of these so far incurable diseases.
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Abstract
Alport syndrome is a hereditary, progressive, hematuric nephropathy characterized by glomerular basement membrane abnormalities with frequent hearing defects and ocular anomalies. The disease is associated with mutations in genes encoding the alpha3, alpha4, or alpha5 chains of type IV collagen, COL4A3, or COL4A4 in the autosomal forms of the disease, COL4A5 in the more frequent X-linked variety. Ultrastructural changes in the glomerular basement membrane and frequent abnormal expression of type IV collagen chains in renal and skin basement membranes are crucial elements for the diagnosis of Alport syndrome, determination of the mode of inheritance, and genetic counseling. Animal models have provided invaluable tools to study the mechanisms leading to progressive deterioration of the glomerular basement membrane and ultimately to renal failure, and to evaluate benefits of potential targeted therapies.
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Affiliation(s)
- Laurence Heidet
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte and Inserm U574, Hôpital Necker-Enfants Malades AP-HP, Paris, France
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35
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Abrahamson DR, Hudson BG, Stroganova L, Borza DB, St John PL. Cellular origins of type IV collagen networks in developing glomeruli. J Am Soc Nephrol 2009. [PMID: 19423686 DOI: 10.1681/asn.2008101086.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen alpha 1 alpha 2 alpha1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen alpha 3 alpha 4 alpha 5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen alpha 3 alpha 4 alpha 5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen alpha 5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen alpha 3 alpha 4 alpha 5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type.
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Affiliation(s)
- Dale R Abrahamson
- Department of Anatomy and Cell Biology, The Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 3038, Kansas City, KS 66160, USA.
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36
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Abrahamson DR, Hudson BG, Stroganova L, Borza DB, St John PL. Cellular origins of type IV collagen networks in developing glomeruli. J Am Soc Nephrol 2009; 20:1471-9. [PMID: 19423686 DOI: 10.1681/asn.2008101086] [Citation(s) in RCA: 150] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen alpha 1 alpha 2 alpha1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen alpha 3 alpha 4 alpha 5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen alpha 3 alpha 4 alpha 5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen alpha 5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen alpha 3 alpha 4 alpha 5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type.
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Affiliation(s)
- Dale R Abrahamson
- Department of Anatomy and Cell Biology, The Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 3038, Kansas City, KS 66160, USA.
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Gross O, Borza DB, Anders HJ, Licht C, Weber M, Segerer S, Torra R, Gubler MC, Heidet L, Harvey S, Cosgrove D, Lees G, Kashtan C, Gregory M, Savige J, Ding J, Thorner P, Abrahamson DR, Antignac C, Tryggvason K, Hudson B, Miner JH. Stem cell therapy for Alport syndrome: the hope beyond the hype. Nephrol Dial Transplant 2008; 24:731-4. [PMID: 19110486 DOI: 10.1093/ndt/gfn722] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Oliver Gross
- Department of Nephrology and Rheumatology, University Hospital Gottingen, Gottingen, Germany.
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38
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LeBleu VS, Kalluri R. Stem Cell–Based Therapy for Glomerular Diseases: An Evolving Concept. J Am Soc Nephrol 2008; 19:1621-3. [DOI: 10.1681/asn.2008070735] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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