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Mahrous NN, Jamous YF, Almatrafi AM, Fallatah DI, Theyab A, Alanati BH, Alsagaby SA, Alenazi MK, Khan MI, Hawsawi YM. A Current Landscape on Alport Syndrome Cases: Characterization, Therapy and Management Perspectives. Biomedicines 2023; 11:2762. [PMID: 37893135 PMCID: PMC10604007 DOI: 10.3390/biomedicines11102762] [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: 09/09/2023] [Revised: 09/30/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
Alport syndrome (AS) is a rare genetic disorder categorized by the progressive loss of kidney function, sensorineural hearing loss and eye abnormalities. It occurs due to mutations in three genes that encode for the alpha chains of type IV collagen. Globally, the disease is classified based on the pattern of inheritance into X-linked AS (XLAS), which is caused by pathogenic variants in COL4A5, representing 80% of AS. Autosomal recessive AS (ARAS), caused by mutations in either COL4A3 or COL4A4, represents 15% of AS. Autosomal dominant AS (ADAS) is rare and has been recorded in 5% of all cases due to mutations in COL4A3 or COL4A4. This review provides updated knowledge about AS including its clinical and genetic characteristics in addition to available therapies that only slow the progression of the disease. It also focuses on reported cases in Saudi Arabia and their prevalence. Moreover, we shed light on advances in genetic technologies like gene editing using CRISPR/Cas9 technology, the need for an early diagnosis of AS and managing the progression of the disease. Eventually, we provide a few recommendations for disease management, particularly in regions like Saudi Arabia where consanguineous marriages increase the risk.
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Affiliation(s)
- Nahed N. Mahrous
- Department of Biological Sciences, College of Science, University of Hafr Al-Batin, Hafr Al-Batin 39524, Saudi Arabia;
| | - Yahya F. Jamous
- The National Center of Vaccines and Bioprocessing, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia;
| | - Ahmad M. Almatrafi
- Department of Biological Sciences, College of Science, Taibah University, Madinah 42353, Saudi Arabia;
| | - Deema I. Fallatah
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Abdulrahman Theyab
- Department of Laboratory and Blood Bank, Security Forces Hospital, Makkah 11481, Saudi Arabia;
- Department of Biochemistry & Molecular Medicine, College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia
| | - Bayan H. Alanati
- Center for Synthetic Microbiology, Bioinformatics Core Facility, University of Marburg, 35032 Marburg, Germany;
| | - Suliman A. Alsagaby
- Department of Medicinal Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia;
| | - Munifa K. Alenazi
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; (M.K.A.); (M.I.K.)
| | - Mohammed I. Khan
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; (M.K.A.); (M.I.K.)
| | - Yousef M. Hawsawi
- Department of Biochemistry & Molecular Medicine, College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; (M.K.A.); (M.I.K.)
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Basement membrane collagens and disease mechanisms. Essays Biochem 2019; 63:297-312. [PMID: 31387942 PMCID: PMC6744580 DOI: 10.1042/ebc20180071] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 07/09/2019] [Accepted: 07/22/2019] [Indexed: 12/28/2022]
Abstract
Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major BM collagen, collagens VI, VII, XV, XVII and XVIII are also present. Mutations in these collagens cause rare multi-systemic diseases but these collagens have also been associated with major common diseases including stroke. Developing treatments for these conditions will require a collective effort to increase our fundamental understanding of the biology of these collagens and the mechanisms by which mutations therein cause disease. Novel insights into pathomolecular disease mechanisms and cellular responses to these mutations has been exploited to develop proof-of-concept treatment strategies in animal models. Combined, these studies have also highlighted the complexity of the disease mechanisms and the need to obtain a more complete understanding of these mechanisms. The identification of pathomolecular mechanisms of collagen mutations shared between different disorders represent an attractive prospect for treatments that may be effective across phenotypically distinct disorders.
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Abstract
In this commentary, I review recent advances in Alport syndrome genetics, diagnostics, and therapeutics. I also offer some opinions regarding strategies to optimize the early identification of affected individuals to promote early therapeutic intervention.
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Affiliation(s)
- Clifford Kashtan
- Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Medical School, Minneapolis, MN, USA
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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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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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Moodley K, Naidoo Y, Mackraj I. Effects of Tulbaghia violacea Harv. (Alliaceae) rhizome methanolic extract on kidney function and morphology in Dahl salt-sensitive rats. JOURNAL OF ETHNOPHARMACOLOGY 2014; 155:1194-1203. [PMID: 25017374 DOI: 10.1016/j.jep.2014.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 06/12/2014] [Accepted: 07/01/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tulbaghia violacea has been used traditionally for the treatment of several ailments, including hypertension. The herb has been shown to have antihypertensive properties which have been attributed to its angiotensin-converting enzymeinhibitory (ACEI) activity. It could, therefore, prove beneficial in ameliorating renal pathology associated with hypertension. To evaluate the effects of long-term administration of Tulbaghia violacea on renal function and morphology in the Dahl salt-sensitive (DSS) rat model. MATERIALS AND METHODS Male DSS rats were treated intra-peritoneally (i.p.) as follows: methanolic extract of Tulbaghia violacea: (TVL) (50 mg/kg/b.w.), captopril: (CAP) (25 mg/kg/b.w.), or distilled water, control: (CON) (3 ml/kg/b.w.). Blood pressure (BP) was measured bi-weekly, whilst 24-h urine volumes and electrolyte concentrations were assessed weekly. Animals were sacrificed on day 49 by halothane overdose. Blood was removed for determination of plasma and serum electrolytes. Left kidney tissues were harvested for the determination of nuclear factor-kappaβ (NF-kβ) and transforming growth factor-β (TGF-β) gene expressions. RESULTS TVL significantly reduced mean arterial pressure (MAP) and diastolic blood pressure (DBP). TVL showed reduced blood urea nitrogen, serum creatinine, total protein in urine as well as increased serum total protein. TVL decreased thiobarbituric acid reactive substances (TBARS) and increased glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity and nitric oxide significantly. NF-kβ and TGF-β) gene expressions were significantly reduced in TVL and CAP treated rats. Moreover, renal morphology improved significantly in TVL and CAP treated animals. CONCLUSION TVL and CAP demonstrated marked improvement in renal function and morphology.
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Affiliation(s)
- Kogi Moodley
- Department of Human Physiology, School of Basic Medical Sciences, Faculty of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
| | - Yougasphree Naidoo
- Department of Biology, School of Biological and Conservation Sciences, Faculty of Science and Agriculture, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
| | - Irene Mackraj
- Department of Human Physiology, School of Basic Medical Sciences, Faculty of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa.
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Noone D, Licht C. Chronic kidney disease: a new look at pathogenetic mechanisms and treatment options. Pediatr Nephrol 2014; 29:779-92. [PMID: 23471475 DOI: 10.1007/s00467-013-2436-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 01/31/2013] [Accepted: 02/06/2013] [Indexed: 12/16/2022]
Abstract
The concept of renoprotection has evolved significantly, driven by improved understanding of the pathophysiology of chronic kidney disease (CKD) and the advent of novel treatment options. Glomerular hyperfiltration, hypertension and proteinuria represent key mediators of CKD progression. It is increasingly recognized that proteinuria may actually be pathological and etiological in CKD progression and not just symptomatic. It initiates a sequence of events involving activation of proinflammatory and profibrotic signaling pathways in proximal tubular epithelial cells with transmission of the disease to the tubulointerstitium and progression to end-stage kidney disease (ESKD). Although the etiology and epidemiology of pediatric CKD differs to that in adults, studies in the various animal models of kidney disease, from obstructive uropathy to glomerulonephritis, have revealed that many common proinflammatory and profibrotic pathways are induced in progressive proteinuric CKD, irrespective of the primary disease. This pathomechanistic overlap therefore translates into the potential for common treatment targets for a wide spectrum of kidney diseases. In this review we therefore discuss the experimental and clinical evidence for an array of prospective future drug treatments of CKD progression. While conceptually promising, clear definitive evidence beyond preclinical data does not exist for many of these treatments, and others are limited by serious adverse effects. More studies are needed before general recommendations can be given.
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Affiliation(s)
- Damien Noone
- Division of Nephrology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, ON, Canada
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Rubel D, Frese J, Martin M, Leibnitz A, Girgert R, Miosge N, Eckes B, Müller GA, Gross O. Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2beta1 delays kidney fibrosis in COL4A3 knockout mice. Matrix Biol 2014; 34:13-21. [PMID: 24480069 DOI: 10.1016/j.matbio.2014.01.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 01/15/2014] [Accepted: 01/16/2014] [Indexed: 02/06/2023]
Abstract
Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes proteinuria and renal fibrosis in the type IV collagen disease Alport syndrome. This study evaluates the role of collagen receptors in maturation of the GBM, matrix accumulation and renal fibrosis by using mice deficient for discoidin domain receptor 1 (DDR1), integrin subunit α2 (ITGA2), and type IV collagen α3 (COL4A3). Loss of both collagen receptors DDR1 and integrin α2β1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes proteinuria to drop down to one tenth until day 200. Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM-maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as Alport syndrome, loss of integrin α2β1 positively delays renal fibrosis: COL4A3(-/-)/ITGA2(-/-) double knockouts exhibited reduced proteinuria and urea nitrogen compared to COL4A3(-/-)/ITGA2(+/-) and COL4A3(-/-)/ITGA2(+/+) mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3(-/-) Alport mice with normal integrin α2β1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3(-/-)/ITGA2(+/+) Alport mice, but not in COL4A3(+/+)/ITGA2(-/-) mice. In conclusion, the collagen receptors DDR1 and integrin α2β1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the type IV collagen disease Alport syndrome, glomerular cell-matrix interactions via collagen receptors play an important role in the progression of renal fibrosis.
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Affiliation(s)
- Diana Rubel
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
| | - Jenny Frese
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany; Dept. of Prosthodontics, Tissue Regeneration Work Group, University Medicine Goettingen, Goettingen, Germany
| | - Maria Martin
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
| | - Alexander Leibnitz
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
| | - Rainer Girgert
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
| | - Nicolai Miosge
- Dept. of Prosthodontics, Tissue Regeneration Work Group, University Medicine Goettingen, Goettingen, Germany
| | - Beate Eckes
- Dept. of Dermatology, University of Cologne, Cologne, Germany
| | - Gerhard-Anton Müller
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
| | - Oliver Gross
- Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany.
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Rubel D, Stock J, Ciner A, Hiller H, Girgert R, Müller GA, Gross O. Antifibrotic, nephroprotective effects of paricalcitol versus calcitriol on top of ACE-inhibitor therapy in the COL4A3 knockout mouse model for progressive renal fibrosis. Nephrol Dial Transplant 2013; 29:1012-9. [PMID: 24198271 DOI: 10.1093/ndt/gft434] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The COL4A3-/- mouse serves as animal model for progressive renal fibrosis. Using this animal model, the present study investigates the nephroprotective effects of Paricalcitol versus Calcitriol alone and on top of ACE-inhibitor therapy. METHODS Eighty six mice were divided into six groups: (PC) with Paricalcitol 0.1 mcg/kg, (CA) Calcitriol 0.03 mcg/kg (dose equipotent), (PLAC) vehicle 0.1 mL i.p. five times per week, (ACE + PC) Paricalcitol plus Ramipril, (ACE + CA) Calcitriol plus Ramipril and (ACE + PLAC) vehicle plus Ramipril 10 mg/kg/day p.o. ACE therapy started pre-emptively in Week 4, PC/CA therapy was initiated in 6-week-old animals with ongoing renal fibrosis and lasted for 8 weeks. Four to six animals were sacrificed after 9.5 weeks and kidneys were further investigated using histological, immunohistological and Western-blot techniques. Survival until end-stage renal failure was determined in the remaining animals. RESULTS PC, but not CA, prolonged lifespan until renal failure by 13% compared with untreated controls (P = 0.069). ACE-inhibition prolonged lifespan by >50%. Added on top of ACE inhibition, ACE + PC (but not ACE + CA) even further prolonged lifespan by additional 18.0% (P < 0.01 versus ACE + PLAC) and improved renal function (blood urea nitrogen; P < 0.05 versus ACE + CA). Accumulation of extracellular matrix and renal scarring was decreased in PC and ACE + PC-treated mice. CONCLUSIONS The present study demonstrated a substantial nephroprotective and antifibrotic effect of the vitamin D-receptor activator Paricalcitol on top of early ACE inhibition in the COL4A3-/- model of progressive kidney fibrosis. The synergistic effect of Paricalcitol on top of RAAS-blockade might as well be valuable in other chronic kidney diseases.
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Affiliation(s)
- Diana Rubel
- Department of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany
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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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Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 2013; 24:364-75. [PMID: 23349312 DOI: 10.1681/asn.2012020148] [Citation(s) in RCA: 235] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.
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Affiliation(s)
- Judy Savige
- Department of Medicine (Northern Health), University of Melbourne, Melbourne, Australia.
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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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Ryu M, Migliorini A, Miosge N, Gross O, Shankland S, Brinkkoetter PT, Hagmann H, Romagnani P, Liapis H, Anders HJ. Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury. J Pathol 2012; 228:482-94. [PMID: 22553158 DOI: 10.1002/path.4046] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 04/19/2012] [Accepted: 04/23/2012] [Indexed: 12/13/2022]
Abstract
Glomerular crescents are most common in rapidly progressive glomerulonephritis but also occur in non-inflammatory chronic glomerulopathies; thus, factors other than inflammation should trigger crescent formation, eg vascular damage and plasma leakage. Here we report that Alport nephropathy in Col4A3-deficient Sv129 mice is complicated by diffuse and global crescent formation in which proliferating parietal epithelial cells are the predominant cell type. Laminin staining and transmission and acellular scanning electron microscopy of acellular glomeruli documented disruptions and progressive disintegration of the glomerular basement membrane in Col4A3-deficient mice. FITC-dextran perfusion further revealed vascular leakage from glomerular capillaries into Bowman's space, further documented by fibrin deposits in the segmental crescents. Its pathogenic role was validated by showing that the fibrinolytic activity of recombinant urokinase partially prevented crescent formation. In addition, in vitro studies confirmed an additional mitogenic potential of serum on murine and human parietal epithelial cells. Furthermore, loss of parietal cell polarity and unpolarized secretion of extracellular matrix components were evident within fibrocellular crescents. Among 665 human Alport nephropathy biopsies, crescent formation was noted in 0.4%. We conclude that glomerular vascular injury and GBM breaks cause plasma leakage which triggers a wound healing programme involving the proliferation of parietal cells and their loss of polarity. This process can trigger cellular and fibrocellular crescent formation even in the absence of cellular inflammation and rupture of the Bowman's capsule.
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Affiliation(s)
- Mi Ryu
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Germany
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Petrova DT, Brehmer F, Schultze FC, Asif AR, Gross O, Oellerich M, Brandhorst G. Differential Kidney Proteome Profiling in a Murine Model of Renal Fibrosis under Treatment with Mycophenolate Mofetil. Pathobiology 2011; 78:162-70. [DOI: 10.1159/000324597] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Accepted: 01/25/2011] [Indexed: 01/29/2023] Open
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Gross O, Girgert R, Rubel D, Temme J, Theissen S, Muller GA. Renal protective effects of aliskiren beyond its antihypertensive property in a mouse model of progressive fibrosis. Am J Hypertens 2011; 24:355-61. [PMID: 21127470 DOI: 10.1038/ajh.2010.231] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The direct renin inhibitor aliskiren is known to exhibit a strong antihypertensive effect. However, the organoprotective potential of aliskiren beyond its antihypertensive properties is less clear. This study investigates the antifibrotic nephroprotective effects of aliskiren in a nonhypertensive mouse model for progressive renal fibrosis. METHODS COL4A3(-/-) mice received aliskiren via osmotic minipumps. Placebo-treated animals served as controls. Therapy was initiated in 6-week-old animals already showing renal damage (proteinuria ~1 g/l, starting renal fibrosis) and lasted for 4 weeks. Six animals were sacrificed after 9.5 weeks; serum urea and proteinuria were measured. Kidneys were further investigated using histological, immunohistological, and western blot techniques. Survival until end-stage renal failure was monitored in the remaining animals. RESULTS COL4A3(-/-) mice did not develop hypertension. Aliskiren serum levels were in the therapeutic range (288 ± 44 ng/ml). Therapy significantly prolonged lifespan until death from renal failure by 18% compared with placebo-treated controls (78.6 ± 8.2 vs. 66.6 ± 4.9 days, P < 0.05). Similarly, therapy reduced the amount of proteinuria and serum urea. Compared with placebo-treated controls, the accumulation of extracellular matrix and renal scarring and the levels of transforming growth factor-β (TGFβ) and connective tissue growth factor (CTGF) were decreased in treated mice. CONCLUSIONS Despite the late onset of therapy, our results indicate nephroprotective effects of the renin inhibitor aliskiren beyond its antihypertensive property in this animal model of progressive renal fibrosis. In addition to the recognized antihypertensive action of aliskiren, its antifibrotic, antiproteinuric effects demonstrated in the present study indicate that aliskiren may have potential as an important therapeutic option for chronic fibrotic diseases in humans.
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Prunotto M, Gabbiani G, Pomposiello S, Ghiggeri G, Moll S. The kidney as a target organ in pharmaceutical research. Drug Discov Today 2011; 16:244-59. [DOI: 10.1016/j.drudis.2010.11.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Revised: 11/11/2010] [Accepted: 11/24/2010] [Indexed: 02/07/2023]
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Abstract
Hematuria is a common presenting complaint in pediatric nephrology clinics and often has a familial basis. This teaching article provides an overview of causes, diagnosis, and management of the major forms of familial hematuria, Alport syndrome, and thin basement membrane nephropathy.
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Affiliation(s)
- Clifford E Kashtan
- Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Medical School, University of Minnesota Children's Hospital, Fairview, Minneapolis, MN 55455, USA.
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Gubler MC. Diagnosis of Alport syndrome without biopsy? Pediatr Nephrol 2007; 22:621-5. [PMID: 17143627 DOI: 10.1007/s00467-006-0376-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2006] [Revised: 10/23/2006] [Accepted: 10/25/2006] [Indexed: 01/18/2023]
Abstract
Alport syndrome (AS) is genetically heterogeneous. The gene COL4A5 is mutated in the more frequent X-linked dominant form of the disease whereas COL4A3 or COL4A4 are mutated in the autosomal recessive and dominant forms. Diagnosis of AS and determination of the mode of transmission are important because of the differences in prognosis and genetic counselling attached to these different forms. Recently, promising results have been obtained in Col4a3-null mice, an animal model for AS, with different therapeutic trials when administered early in the course of the disease, an additional reason for making early diagnosis of AS in children. Since the identification of the molecular basis of the disease, mutation screening is theoretically the best diagnostic approach, avoiding the use or renal or skin biopsy. However, for many reasons linked to the genetic heterogeneity of the disease, the large size of the three genes and the random distribution of the mutations all along these huge genes, this method is tedious, expensive and time consuming. Moreover, its sensitivity is reduced. For these reasons, evaluation of the expression of type IV collagen chains in the skin, and if necessary in the renal basement membrane, remains a useful tool for AS diagnosis. At this time, the indication for these different approaches, which are not mutually exclusive but complementary, depends on the patient clinical presentation and family history.
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Affiliation(s)
- Marie Claire Gubler
- INSERM U543, Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France.
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Quaschning T, Hocher B, Ruhl S, Kraemer-Guth A, Tilgner J, Wanner C, Galle J. Vasopeptidase inhibition normalizes blood pressure and restores endothelial function in renovascular hypertension. Kidney Blood Press Res 2006; 29:351-9. [PMID: 17139187 DOI: 10.1159/000097625] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2006] [Accepted: 10/27/2006] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension. METHODS Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively. RESULTS Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups. CONCLUSION In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.
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Affiliation(s)
- Thomas Quaschning
- Department of Nephrology, University Hospital of Freiburg, Freiburg, Germany.
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Beirowski B, Weber M, Gross O. Chronic renal failure and shortened lifespan in COL4A3+/- mice: an animal model for thin basement membrane nephropathy. J Am Soc Nephrol 2006; 17:1986-94. [PMID: 16775036 DOI: 10.1681/asn.2005101044] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.
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Affiliation(s)
- Bogdan Beirowski
- Medical Faculty University of Cologne, Medicine Clinic I, Hospital Merheim, Ostmerheimer Strasse 200, D-51109 Cologne, Germany
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Battistini B, Daull P, Jeng AY. CGS 35601, a Triple Inhibitor of Angiotensin Converting Enzyme, Neutral Endopeptidase and Endothelin Converting Enzyme. ACTA ACUST UNITED AC 2006; 23:317-30. [PMID: 16614731 DOI: 10.1111/j.1527-3466.2005.tb00175.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CGS 35601 (L-tryptophan, N-[[1-[[(2S)-2-mercapto-4-methyl-1-oxopentyl]amino]-cyclopentyl]carbonyl]) is one of a few single molecules capable of inhibiting the activities of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) simultaneously, with IC(50) values of 22, 2, and 55 nM, respectively. Through the inhibition of ACE and ECE, it blocks the conversion of angiotensin I (AI) and big endothelin-1 (big ET-1) into the two most potent peptidic vasoconstrictors, angiotensin II (AII) and ET-1, respectively. By inhibiting NEP, CGS 35601 also prevents the degradation of peptidic vasodilators such as bradykinin (BK), natriuretic peptides (NPs) and adrenomedullin (ADM) and, hence, modulates the secondary release of other vasoactive mediators such as nitric oxide (NO) and prostaglandins. In chronic (30 days) experiments, CGS 35601 is well tolerated with a very good safety profile in healthy normotensive, hypertensive and type 2 diabetic rats. The antihypertensive efficacy of CGS 35601 was demonstrated in chronically instrumented, unrestrained and conscious rat models of hypertension (SHR and DSS) and type 2 diabetes (ZDF-fatty). It lowered blood pressure effectively as well as modulated plasma concentrations of a number of circulating vasoactive peptidic mediators that are keys to the regulation of the vascular tone. These data suggest that CGS 35601, a triple vasopeptidase inhibitor (VPI), may represent a novel class of antihypertensive drugs and may have the potential to reduce morbidity and mortality from cardiovascular disorders, diabetes and subsequent renal complications. Similar in vivo ACE, NEP, and ECE inhibitory activities were also observed with the orally active prodrug, CGS 37808 (L-tryptophan, N-[[1-[[(2S)-2-(acetylthio)-4-methyl-1-oxopentyl]amino]cyclopentyl]-carbonyl]-, methyl ester.
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Affiliation(s)
- Bruno Battistini
- Laval Hospital Research Center, Quebec Heart and Lung Institute, Department of Medicine, Laval University, Ste-Foy, QC G1V 4G5, Canada.
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Ninichuk V, Gross O, Segerer S, Hoffmann R, Radomska E, Buchstaller A, Huss R, Akis N, Schlöndorff D, Anders HJ. Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. Kidney Int 2006; 70:121-9. [PMID: 16723981 DOI: 10.1038/sj.ki.5001521] [Citation(s) in RCA: 210] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Multipotent mesenchymal stem or stromal cells (MSC) have shown to improve outcome of acute renal injury models, but whether MSC can delay renal failure in chronic kidney disease is not known. We injected primary MSC or saline into mice that lack the alpha3-chain of type IV collagen (COL4A3), a model of chronic kidney disease with close similarities to human Alport disease. Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice. However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections. Although MSC were found to localize to kidneys of COL4A3-deficient mice after injection, differentiation into renal cells was not detected. However, MSC expressed growth factors, that is, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 under basal culture conditions. In fact, VEGF mRNA levels were increased in kidneys of MSC-injected COL4A3-deficient mice and MSC supernatants enhance endothelial cell proliferation in vitro. Thus, weekly injections with MSC prevent loss of peritubular capillaries possibly owing to local production of growth factors rather than by differentiation into renal cells. The maintenance of interstitial vasculature is associated with less interstitial fibrosis but, is insufficient to delay renal failure and survival of COL4A3-deficient mice.
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Affiliation(s)
- V Ninichuk
- Medical Polyclinic, Nephrological Center, University of Munich, Munich, Germany
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Kikkawa K. [Antihypertensive drugs in clinical development]. Nihon Yakurigaku Zasshi 2006; 127:381-6. [PMID: 16819244 DOI: 10.1254/fpj.127.381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
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