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Juarez-Villa JD, Zepeda-Quiroz I, Toledo-Ramírez S, Gomez-Johnson VH, Pérez-Allende F, Garibay-Vega BR, Rodríguez Castellanos FE, Moguel-González B, Garcia-Cruz E, Lopez-Gil S. Exploring kidney biopsy findings in congenital heart diseases: Insights beyond cyanotic nephropathy. World J Nephrol 2024; 13:88972. [PMID: 38596269 PMCID: PMC11000040 DOI: 10.5527/wjn.v13.i1.88972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/20/2023] [Accepted: 01/15/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND The association between congenital heart disease and chronic kidney disease is well known. Various mechanisms of kidney damage associated with congenital heart disease have been established. The etiology of kidneydisease has commonly been considered to be secondary to focal segmental glomerulosclerosis (FSGS), however, this has only been demonstrated in case reports and not in observational or clinical trials. AIM To identify baseline and clinical characteristics, as well as the findings in kidney biopsies of patients with congenital heart disease in our hospital. METHODS This is a retrospective observational study conducted at the Nephrology Department of the National Institute of Cardiology "Ignacio Chávez". All patients over 16 years old who underwent percutaneous kidney biopsy from January 2000 to January 2023 with congenital heart disease were included in the study. RESULTS Ten patients with congenital heart disease and kidney biopsy were found. The average age was 29.00 years ± 15.87 years with pre-biopsy proteinuria of 6193 mg/24 h ± 6165 mg/24 h. The most common congenital heart disease was Fallot's tetralogy with 2 cases (20%) and ventricular septal defect with 2 (20%) cases. Among the 10 cases, one case of IgA nephropathy and one case of membranoproliferative glomerulonephritis associated with immune complexes were found, receiving specific treatment after histopathological diagnosis, delaying the initiation of kidney replacement therapy. Among remaining 8 cases (80%), one case of FSGS with perihilar variety was found, while the other 7 cases were non-specific FSGS. CONCLUSION Determining the cause of chronic kidney disease can help in delaying the need for kidney replacement therapy. In 2 out of 10 patients in our study, interventions were performed, and initiation of kidney replacement therapy was delayed. Prospective studies are needed to determine the usefulness of kidney biopsy in patients with congenital heart disease.
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Affiliation(s)
- Jose Daniel Juarez-Villa
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Iván Zepeda-Quiroz
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Sebastián Toledo-Ramírez
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Victor Hugo Gomez-Johnson
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Francisco Pérez-Allende
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | | | | | - Bernardo Moguel-González
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Edgar Garcia-Cruz
- Congenital Heart Disease, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Salvador Lopez-Gil
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
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Sabatino J, Avesani M, Sirico D, Reffo E, Castaldi B, Bassareo P, Di Salvo G. Systemic hypertension in adults with congenital heart diseases. INTERNATIONAL JOURNAL OF CARDIOLOGY CONGENITAL HEART DISEASE 2023; 13:100456. [PMID: 39712235 PMCID: PMC11658137 DOI: 10.1016/j.ijcchd.2023.100456] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 12/24/2024] Open
Abstract
Long-term effects of systemic hypertension (HTN) and HTN-mediated damages have been largely studied in non-congenital adult populations. By contrast, robust data about the predisposing factors, prevalence, consequences, and treatment of HTN in adults with congenital heart diseases (ACHD) is still scarce. Different mechanisms including the underlying cardiac disease, cardiac surgery and its consequences, the development of metabolic syndrome and secondary forms seem to play a role in HTN in ACHDs. To mitigate the potential long-term effects of HTN in this complex population, a meticulous follow-up is mandatory to identify patients who should receive treatment, and tailored strategies should be applied to obtain the best as possible result. Thus, this review will investigate risk factors, effects, and treatments of HTN in ACHD patients.
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Affiliation(s)
- Jolanda Sabatino
- Department of Women's and Children's Health, University of Padua, Padua, Italy
- Paediatric Research Institute (IRP), Città Della Speranza, 35127, Padua, Italy
| | - Martina Avesani
- Department of Women's and Children's Health, University of Padua, Padua, Italy
- Paediatric Research Institute (IRP), Città Della Speranza, 35127, Padua, Italy
| | - Domenico Sirico
- Department of Women's and Children's Health, University of Padua, Padua, Italy
- Paediatric Research Institute (IRP), Città Della Speranza, 35127, Padua, Italy
| | - Elena Reffo
- Department of Women's and Children's Health, University of Padua, Padua, Italy
- Paediatric Research Institute (IRP), Città Della Speranza, 35127, Padua, Italy
| | - Biagio Castaldi
- Department of Women's and Children's Health, University of Padua, Padua, Italy
- Paediatric Research Institute (IRP), Città Della Speranza, 35127, Padua, Italy
| | - PierPaolo Bassareo
- Unit of Adult Congenital Heart Disease, University College of Dublin, Dublin, Ireland
| | - Giovanni Di Salvo
- Department of Women's and Children's Health, University of Padua, Padua, Italy
- Paediatric Research Institute (IRP), Città Della Speranza, 35127, Padua, Italy
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Huynh L, Rodriguez-Lopez S, Benisty K, Dancea A, Garros D, Hessey E, Joffe A, Joffe R, Mackie A, Palijan A, Paun A, Pizzi M, Zappitelli M, Morgan C. Follow-up after neonatal heart disease repair: watch out for chronic kidney disease and hypertension! Pediatr Nephrol 2020; 35:2137-2145. [PMID: 32500246 PMCID: PMC7515960 DOI: 10.1007/s00467-020-04621-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 05/01/2020] [Accepted: 05/19/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND With advances in care, neonates undergoing cardiac repairs are surviving more frequently. Our objectives were to 1) estimate the prevalence of chronic kidney disease (CKD) and hypertension 6 years after neonatal congenital heart surgery and 2) determine if cardiac surgery-associated acute kidney injury (CS-AKI) is associated with these outcomes. METHODS Two-center prospective, longitudinal single-visit cohort study including children with congenital heart disease surgery as neonates between January 2005 and December 2012. CKD (estimated glomerular filtration rate < 90 mL/min/1.73m2 or albumin/creatinine ≥3 mg/mmol) and hypertension (systolic or diastolic blood pressure ≥ 95th percentile for age, sex, and height) prevalence 6 years after surgery was estimated. The association of CS-AKI (Kidney Disease: Improving Global Outcomes definition) with CKD and hypertension was determined using multiple regression. RESULTS Fifty-eight children with median follow-up of 6 years were evaluated. CS-AKI occurred in 58%. CKD and hypertension prevalence were 17% and 30%, respectively; an additional 15% were classified as having elevated blood pressure. CS-AKI was not associated with CKD or hypertension. Classification as cyanotic postoperatively was the only independent predictor of CKD. Postoperative days in hospital predicted hypertension at follow-up. CONCLUSIONS The prevalence of CKD and hypertension is high in children having neonatal congenital heart surgery. This is important; early identification of CKD and hypertension can improve outcomes. These children should be systematically followed for the evolution of these negative outcomes. CS-AKI defined by current standards may not be a useful clinical tool to decide who needs follow-up and who does not.
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Affiliation(s)
- Louis Huynh
- Faculty of Health Sciences, School of Medicine, Queen's University, Kingston, ON, Canada
| | - Sara Rodriguez-Lopez
- Department of Pediatrics, Division of Nephrology, University of Alberta, Stollery Children's Hospital, Room 4-555, 11405-87 Avenue, Edmonton, AB, T6G 1C9, Canada
| | - Kelly Benisty
- Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Adrian Dancea
- Department of Pediatrics, Division of Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Daniel Garros
- Department of Pediatrics, Division of Pediatric Critical Care, University of Alberta, Edmonton, AB, Canada
| | - Erin Hessey
- Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Ari Joffe
- Department of Pediatrics, Division of Pediatric Critical Care, University of Alberta, Edmonton, AB, Canada
| | - Rachel Joffe
- Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Andrew Mackie
- Department of Pediatrics, Division of Cardiology, University of Alberta, Edmonton, AB, Canada
| | - Ana Palijan
- McGill University Health Centre Research Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Alex Paun
- McGill University Health Centre Research Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Michael Pizzi
- McGill University Health Centre Research Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Michael Zappitelli
- Department of Pediatrics, Division of Nephrology, Peter Gilgan Centre for Research and Learning, Toronto Hospital for Sick Children, 686 Bay Street, Room 6th floor 9708, Toronto, ON, M5G 0A4, Canada.
| | - Catherine Morgan
- Department of Pediatrics, Division of Nephrology, University of Alberta, Stollery Children's Hospital, Room 4-555, 11405-87 Avenue, Edmonton, AB, T6G 1C9, Canada.
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Ponikowska M, Pollak A, Kotwica-Strzalek E, Brodowska-Kania D, Mosakowska M, Ploski R, Niemczyk S. Peritoneal dialysis in an adult patient with tetralogy of Fallot diagnosed with incomplete Alagille syndrome. BMC MEDICAL GENETICS 2020; 21:195. [PMID: 33008311 PMCID: PMC7532568 DOI: 10.1186/s12881-020-01134-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 09/27/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Alagille syndrome is an autosomal dominant disorder usually caused by pathogenic variants of the JAG1 gene. In the past, cholestasis was a condition sine qua non for diagnosis of the syndrome. However, recent advancements in genetic testing have revealed that clinical presentations vary from lack of symptoms, to multiorgan involvement. Tetralogy of Fallot, the most frequent complex congenital heart defect in Alagille Syndrome, very rarely leads to renal failure requiring dialysis - there are only single reports of such cases in the literature, with none of them in Alagille Syndrome. CASE PRESENTATION A 41-year-old woman suffering from cyanosis, dyspnea and plethora was admitted to the hospital. The patient suffered from chronic kidney disease and tetralogy of Fallot and had been treated palliatively with Blalock-Taussig shunts in the past; at admission, only minimal flow through the left shunt was preserved. These symptoms, together with impaired mental status and dysmorphic facial features, led to extensive clinical and genetic testing including whole exome sequencing. A previously unknown missense variant c.587G > A within the JAG1 gene was identified. As there were no signs of cholestasis, and subclinical liver involvement was only suggested by elevated alkaline phosphatase levels, the patient was diagnosed with incomplete Alagille Syndrome. End-stage renal disease required introduction of renal replacement therapy. Continuous ambulatory peritoneal dialysis was chosen and the patient's quality of life significantly increased. However, after refusal of further treatment, the patient died at the age of 45. CONCLUSIONS Tetralogy of Fallot should always urge clinicians to evaluate for Alagille Syndrome and offer patients early nephrological care. Although tetralogy of Fallot rarely leads to end-stage renal disease requiring dialysis, if treated palliatively and combined with renal dysplasia (typical of Alagille Syndrome), it can result in severe renal failure as in the presented case. There is no standard treatment for such cases, but based on our experience, peritoneal dialysis is worth consideration. Finally, clinical criteria for the diagnosis of Alagille Syndrome require revision. Previously, diagnosis was based on cholestasis - however, cardiovascular anomalies are found to be more prevalent. Furthermore, the criteria do not include renal impairment, which is also common.
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Affiliation(s)
- Malgorzata Ponikowska
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 128 Szaserów St, 04-141, Warsaw, Poland. .,Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63 St., 80-308, Gdansk, Poland.
| | - Agnieszka Pollak
- Department of Medical Genetics, Medical University of Warsaw, 3c Pawinskiego St., 02-106, Warsaw, Poland
| | - Ewa Kotwica-Strzalek
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 128 Szaserów St, 04-141, Warsaw, Poland
| | - Dorota Brodowska-Kania
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 128 Szaserów St, 04-141, Warsaw, Poland
| | - Magdalena Mosakowska
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 128 Szaserów St, 04-141, Warsaw, Poland
| | - Rafal Ploski
- Department of Medical Genetics, Medical University of Warsaw, 3c Pawinskiego St., 02-106, Warsaw, Poland
| | - Stanislaw Niemczyk
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 128 Szaserów St, 04-141, Warsaw, Poland
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Morgan C, Al-Aklabi M, Garcia Guerra G. Chronic kidney disease in congenital heart disease patients: a narrative review of evidence. Can J Kidney Health Dis 2015; 2:27. [PMID: 26266042 PMCID: PMC4531493 DOI: 10.1186/s40697-015-0063-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 07/09/2015] [Indexed: 11/10/2022] Open
Abstract
Purpose of review Patients with congenital heart disease have a number of risk factors for the development of chronic kidney disease (CKD). It is well known that CKD has a large negative impact on health outcomes. It is important therefore to consider that patients with congenital heart disease represent a population in whom long-term primary and secondary prevention strategies to reduce CKD occurrence and progression could be instituted and significantly change outcomes. There are currently no clear guidelines for clinicians in terms of renal assessment in the long-term follow up of patients with congenital heart disease. Consolidation of knowledge is critical for generating such guidelines, and hence is the purpose of this view. This review will summarize current knowledge related to CKD in patients with congenital heart disease, to highlight important work that has been done to date and set the stage for further investigation, development of prevention strategies, and re-evaluation of appropriate renal follow-up in patients with congenital heart disease. Sources of information The literature search was conducted using PubMed and Google Scholar. Findings Current epidemiological evidence suggests that CKD occurs in patients with congenital heart disease at a higher frequency than the general population and is detectable early in follow-up (i.e. during childhood). Best evidence suggests that approximately 30 to 50 % of adult patients with congenital heart disease have significantly impaired renal function. The risk of CKD is higher with cyanotic congenital heart disease but it is also present with non-cyanotic congenital heart disease. Although significant knowledge gaps exist, the sum of the data suggests that patients with congenital heart disease should be followed from an early age for the development of CKD. Implications There is an opportunity to mitigate CKD progression and negative renal outcomes by instituting interventions such as stringent blood pressure control and reduction of proteinuria. There is a need to invest time, thought and money to fill existing knowledge gaps to improve health outcomes in this population. This review should serve as an impetus for generation of follow-up guidelines of kidney health evaluation in patients with congenital heart disease.
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Affiliation(s)
- Catherine Morgan
- Division of Nephrology, Department of Pediatrics, 4-557 Edmonton Clinic Health Academy, 11405 - 87 Avenue, Edmonton, AB T6G 1C9 Canada
| | - Mohammed Al-Aklabi
- Division of Cardiac Surgery, Department of Medicine, 4A7.C Mazankowski Heart Institute, 8440 - 112 Street, Edmonton, AB T6G 2B7 Canada
| | - Gonzalo Garcia Guerra
- Division of Pediatric Critical Care, Department of Pediatrics, 4-548 Edmonton Clinic Health Academy, 11405 - 87 Avenue, Edmonton, AB T6G 1C9 Canada
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Li TT, Zhang XH, Jing JF, Li X, Yang XQ, Zhu FH, Tang W, Zuo JP. Artemisinin analogue SM934 ameliorates the proteinuria and renal fibrosis in rat experimental membranous nephropathy. Acta Pharmacol Sin 2015; 36:188-99. [PMID: 25619396 DOI: 10.1038/aps.2014.134] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/27/2014] [Indexed: 12/14/2022]
Abstract
AIM SM934 is a novel water-soluble artemisinin derivative with immunoregulatory activities that has been used to treat murine lupus nephritis. In the current study, we investigated the effects of SM934 on rat experimental membranous nephropathy. METHODS Passive Heymann nephritis (PHN) was induced in SD rats by intraperitoneal injection of anti-Fx1A serum. The rats were orally administered SM934 (12.5 and 25 mg·kg(-1)·d(-1)) or prednisolone (5 mg·kg(-1)·d(-1)) for 28 d. Blood and urine sample, and kidney tissue were collected for analyses. Human complement C3a-induced injury of HK-2 cells was used for in vitro experiments. RESULTS Treatment of PHN rats with SM934 or prednisolone attenuated the progression of glomerulonephritis and renal fibrosis, as evidenced by the reduced level of proteinuria and circulating antibodies, as well as by the reduced immune complex deposition, reversed podocyte injuries, and attenuated tubulointerstitial fibrosis in the kidneys. Furthermore, the two drugs suppressed TGF-β1 expression and Smad2/3 phosphorylation, and increased Smad7 expression in the kidneys. The two doses of SM934 produced almost identical therapeutic effects on PHN rats. Pretreatment with SM934 or a C3a receptor antagonist blocked the C3a-induced epithelial-mesenchymal transition in HK-2 cells in vitro. CONCLUSION SM934 ameliorates kidney injury and attenuates the tubulointerstitial fibrosis in PHN rats by down-regulation of the TGF-β1/Smad signaling pathway.
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A compendium of urinary biomarkers indicative of glomerular podocytopathy. PATHOLOGY RESEARCH INTERNATIONAL 2013; 2013:782395. [PMID: 24327929 PMCID: PMC3845336 DOI: 10.1155/2013/782395] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 09/10/2013] [Indexed: 12/18/2022]
Abstract
It is well known that glomerular podocyte injury and loss are present in numerous nephropathies and that the pathophysiologic consecution of disease hinges upon the fate of the podocyte. While multiple factors play a hand in glomerulopathy progression, basic logic lends that if one monitors the podocyte's status, that may reflect the status of disease. Recent investigations have focused on what one can elucidate from the noninvasive collection of urine, and have proven that certain, specific biomarkers of podocytes can be readily identified via varying techniques. This paper has brought together all described urinary biomarkers of podocyte injury and is made to provide a concise summary of their utility and testing in laboratory and clinical theatres. While promising in the potential that they hold as tools for clinicians and investigators, the described biomarkers require further comprehensive vetting in the form of larger clinical trials and studies that would give their value true weight. These urinary biomarkers are put forth as novel indicators of glomerular disease presence, disease progression, and therapeutic efficacy that in some cases may be more advantageous than the established parameters/measures currently used in practice.
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van Roeyen CRC, Ostendorf T, Floege J. The platelet-derived growth factor system in renal disease: an emerging role of endogenous inhibitors. Eur J Cell Biol 2011; 91:542-51. [PMID: 21872965 DOI: 10.1016/j.ejcb.2011.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Revised: 07/05/2011] [Accepted: 07/05/2011] [Indexed: 01/28/2023] Open
Abstract
The platelet-derived growth factor (PDGF) family consists of four isoforms which are secreted as homodimers (PDGF-AA, PDGF-BB, PDGF-CC and PDGF-DD) or heterodimers (PDGF-AB), and two receptor chains (PDGFR-α and -β). All members of the PDGF system are constitutively or inducibly expressed in renal cells and are involved in the regulation of cell proliferation and migration, the accumulation of extracellular matrix proteins and the secretion of pro- and anti-inflammatory mediators. Particular roles have been identified in mediating mesangioproliferative changes, renal interstitial fibrosis and glomerular angiogenesis. Different endogenous inhibitors of PDGF-induced biological responses exist which affect the activation/deactivation of PDGF isoforms, the activity of the PDGFRs, or which block downstream signaling pathways of the autophosphorylated PDGFRs. The novel endogenous inhibitor nephroblastoma overexpressed gene (NOV, CCN3) reduces PDGF-induced cell proliferation and is downregulated by PDGF isoforms itself. Among all identified inhibitors only few "true" PDGF antagonists have been identified. A better understanding of these inhibitors may aid in the design of novel therapeutic approaches to PDGF-mediated diseases.
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Affiliation(s)
- Claudia R C van Roeyen
- Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Pauwelsstr. 30, D-52057 Aachen, Germany.
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9
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Rho kinase inhibition protects kidneys from diabetic nephropathy without reducing blood pressure. Kidney Int 2010; 79:432-42. [PMID: 20962741 DOI: 10.1038/ki.2010.428] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Rho-associated kinases (ROCK) are activated in the kidney as well as in cultured cells of diabetic models and have been implicated in renal pathophysiology. To explore whether inhibition of ROCK is protective, we studied its role in a model of accelerated diabetic nephropathy where uninephrectomized rats were made diabetic by streptozotocin. After establishing diabetes, rats were treated with the ROCK inhibitor fasudil continuously or for the final 6 weeks of an 18-week experimental period. The results were compared to similar rats given losartan, an established treatment of clinical and experimental diabetic nephropathy, or a combination of both agents. Vehicle-treated diabetic and non-diabetic uninephrectomized rats served as controls. Diabetes resulted in a rapid development of albuminuria, higher glomerulosclerosis and interstitial fibrosis scores, lower glomerular filtration rates, and increased expression of several molecular markers of diabetic nephropathy. Eighteen weeks of fasudil treatment reduced renal ROCK activity, and ameliorated diabetes-induced structural changes in the kidney and expression of the molecular markers in association with a modest anti-proteinuric effect but no change in blood pressure. Late intervention with fasudil reduced glomerulosclerosis, but did not influence proteinuria. Most effects of fasudil were comparable to those of losartan, although losartan lowered blood pressure and further lowered proteinuria. The combination of both treatments was no different than losartan alone. Thus, ROCK inhibition protected the kidney from diabetic nephropathy even though it did not reduce the blood pressure.
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Floege J, Eitner F, Alpers CE. A New Look at Platelet-Derived Growth Factor in Renal Disease. J Am Soc Nephrol 2007; 19:12-23. [DOI: 10.1681/asn.2007050532] [Citation(s) in RCA: 235] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Neal CR, Muston PR, Njegovan D, Verrill R, Harper SJ, Deen WM, Bates DO. Glomerular filtration into the subpodocyte space is highly restricted under physiological perfusion conditions. Am J Physiol Renal Physiol 2007; 293:F1787-98. [PMID: 17715264 DOI: 10.1152/ajprenal.00157.2007] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Production of urine is initiated by fluid and solute flux across the glomerular filtration barrier. Recent ultrastructural studies have shown that under extreme conditions of no filtration, or very high filtration, a restriction to flow is predicted in a space underneath the podocyte cell body or its processes, the subpodocyte space (SPS). The SPS covered up to two-thirds of the glomerular filtration barrier (GFB) surface. The magnitude of this restriction to flow suggested that it might be unlikely that filtration into and flow through the SPS would contribute significantly to total flow across the entire GFB under these conditions. To determine whether the SPS has similar properties under normal physiological conditions, we have carried out further three-dimensional reconstruction of rat glomeruli perfused at physiologically normal hydrostatic and colloid osmotic pressures. These reconstructions show that the sub-podocyte space is even more restricted under these conditions, with a mean height of the SPS of 0.34 μm, mean pathlength of 6.7 ± 1.4 μm, a mean width of the SPS exit pore of 0.15 ± 0.05 μm, and length of 0.25 ± 0.05 μm. Mathematical modeling of this SPS based on a circular flow model predicts that the resistance of these dimensions is 2.47 times that of the glomerular filtration barrier and exquisitely sensitive to changes in the dimensions of the SPS exit pore (SEP), indicating that the SEP could be the principal regulator of the extravascular pressure in the SPS. This suggests a physiological role of the podocyte in the regulation of glomerular fluid flux across most of the GFB.
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Affiliation(s)
- Christopher R Neal
- Dept. of Physiology, Univ. of Bristol, Southwell St., Bristol BS2 8EJ, UK.
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Griffin KA, Abu-Naser M, Abu-Amarah I, Picken M, Williamson GA, Bidani AK. Dynamic blood pressure load and nephropathy in the ZSF1 (fa/facp) model of type 2 diabetes. Am J Physiol Renal Physiol 2007; 293:F1605-13. [PMID: 17728379 DOI: 10.1152/ajprenal.00511.2006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Diabetes and increased blood pressure (BP) are believed to interact synergistically in the pathogenesis and progression of diabetic nephropathy. The present studies were performed to examine if there were differences in BP load and/or protective renal autoregulatory capacity between the obese diabetic Zucker fatty /spontaneously hypertensive heart failure F1 hybrid (ZSF1) ( fa/ facp) rats and their lean controls. By ∼26 wk of age, ZSF1 ( n = 13) but not their lean controls ( n = 16) had developed substantial proteinuria (180 ± 19 vs. 16 ± 1.4 mg/24 h) and glomerulosclerosis (19 ± 2.4 vs. 0.6 ± 0.2%; P < 0.001). However, average ambient systolic BP by radiotelemetry (12–26 wk of age) was modestly lower in ZSF1 than in lean controls (130 ± 1.4 vs. 137 ± 1.7 mmHg, P < 0.002), although the 24-h BP power spectra showed a mild increase at frequencies <0.1 Hz in the ZSF1. Autoregulatory capacity under anesthesia in response to step changes in perfusion pressure between 100 and 140 mmHg was similarly well preserved in both ZSF1 and lean controls at 16–18 wk of age [autoregulatory indexes (AI) <0.1]. Similarly, differences were not observed for dynamic autoregulation in conscious rats [transfer functions between BP (input) and renal blood flow (output) using chronic Transonic flow probes]. Collectively, these data indicate that the pathogenesis of nephropathy in the ZSF1 model of type 2 diabetic nephropathy is largely independent of differences in systemic BP and/or its potential renal transmission. However, these data do not exclude the possibility that the diabetic milieu may alter the glomerular capillaries in the ZSF1, such that there is an enhanced local susceptibility to injury with even normal glomerular pressures.
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Affiliation(s)
- Karen A Griffin
- Department of Internal Medicine, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153, USA.
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Williams JM, Sharma M, Anjaiahh S, Falck JR, Roman RJ. Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier. Am J Physiol Renal Physiol 2007; 293:F501-5. [PMID: 17507602 PMCID: PMC3146064 DOI: 10.1152/ajprenal.00131.2007] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This study examined the metabolism of arachidonic acid (AA) by cytochrome P-450 enzymes in isolated glomeruli and the effects of selective inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatetraenoic acids (EETs) on glomerular permeability to albumin (P(alb)). Glomeruli avidly produced 20-HETE, EETs, dihydroxyeicosatetraenoic acids (diHETEs), and HETEs when incubated with exogenous AA. N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 microM) selectively inhibited the formation of 20-HETE by 95% and increased P(alb) from 0.00 +/- 0.08 to 0.73 +/- 0.10 (n = 43 glomeruli, 4 rats). Addition of a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (20-5,14-HEDE; 1 microM) opposed the effects of HET0016 (10 microM) to increase P(alb) (0.21 +/- 0.10, n = 36 glomeruli, 4 rats). Preincubation of glomeruli with exogenous AA to increase basal production of 20-HETE had a similar effect. We also examined the effect of an epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MSPPOH; 5 microM), on P(alb). MSPPOH (5 microM) significantly increased P(alb) but had no effect on the synthesis of EETs in glomeruli incubated with AA. However, MSPPOH (5 microM) selectively reduced epoxygenase activity by 50% in glomeruli incubated without added AA. Pretreatment with 8,9-EET (100 nM) attenuated the effects of MSPPOH (5 microM) on P(alb). These results indicate that glomeruli produce 20-HETE, EETs, diHETEs, and HETEs and that endogenously formed 20-HETE and EETs play an essential role in the maintenance of the glomerular permeability barrier to albumin.
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Affiliation(s)
- Jan Michael Williams
- Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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Hiramatsu N, Hiromura K, Shigehara T, Kuroiwa T, Ideura H, Sakurai N, Takeuchi S, Tomioka M, Ikeuchi H, Kaneko Y, Ueki K, Kopp JB, Nojima Y. Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. J Am Soc Nephrol 2007; 18:515-27. [PMID: 17229913 DOI: 10.1681/asn.2006030217] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.
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Affiliation(s)
- Noriyuki Hiramatsu
- Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan
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15
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Bidani AK, Picken M, Hacioglu R, Williamson G, Griffin KA. Spontaneously reduced blood pressure load in the rat streptozotocin-induced diabetes model: potential pathogenetic relevance. Am J Physiol Renal Physiol 2006; 292:F647-54. [PMID: 16968892 PMCID: PMC1794259 DOI: 10.1152/ajprenal.00017.2006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The rat streptozotocin (STZ)-induced diabetes model is widely used to investigate the pathogenesis of diabetic nephropathy. However, overt nephropathy is inexplicably slow to develop in this model compared with renal mass reduction (RMR) models. To examine whether blood pressure (BP) differences correlated with the time course of glomerulosclerosis (GS), BP was measured continuously throughout the course by radiotelemetry in control (n = 17), partially insulin-treated STZ-diabetes (average blood glucose 364 +/- 15 mg/dl; n = 15), and two normotensive RMR models (systolic BP <140 mmHg)--uninephrectomy (UNX; n = 16) and 3/4 RMR by surgical excision [right nephrectomy + excision of both poles of left kidney (RK-NX); n = 12] in Sprague-Dawley rats. Proteinuria and GS were assessed at approximately 16-20 wk (all groups) and at 36-40 wk (all groups except RK-NX). At 16 wk, significantly greater proteinuria and GS had developed in the RK-NX group compared with the other three groups (not different from each other). By 36-40 wk, substantial proteinuria and GS had also developed in the UNX group, but both the control and the STZ-diabetic rats exhibited comparable modest proteinuria and minimal GS. Systolic BP (mmHg) was significantly reduced in the STZ-diabetic rats (116 +/- 1.1) compared with both control (124 +/- 1.0) and RMR (128 +/- 1.2 and 130 +/- 3.0) groups (P < 0.01). Similarly, "BP load" as estimated by BP power spectral analysis was also lower in the STZ-diabetic rats. Given the known protective effects of BP reductions on the progression of diabetic nephropathy, it is likely that this spontaneous reduction in ambient BP contributes to the slow development of GS in the STZ-diabetes model compared with the normotensive RMR models.
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Affiliation(s)
- Anil K Bidani
- Department of Internal Medicine, Loyola University Medical Center, Maywood, IL 60153, USA.
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16
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Neal CR, Crook H, Bell E, Harper SJ, Bates DO. Three-Dimensional Reconstruction of Glomeruli by Electron Microscopy Reveals a Distinct Restrictive Urinary Subpodocyte Space. J Am Soc Nephrol 2005; 16:1223-35. [PMID: 15829713 DOI: 10.1681/asn.2004100822] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
For more than 150 years, the only urinary space that has been recognized in the glomerulus conducting primary filtrate to the proximal convoluted tubule has been Bowman's space (BS) (1). Here it is shown that ultrastructural reconstructions of the podocyte and the glomerulus reveal BS to be formed from three distinct urinary spaces through which filtrate must pass before reaching the proximal convoluted tubule. The most restricted region, the subpodocyte space (SPS; first described by Gautier in 1950), was found to cover 58 to 65% of the glomerular filtration barrier. It is morphologically distinct from the rest of BS and has a highly significant restriction to flow based on morphometric measurements. This SPS was altered during increased renal perfusion pressure, consistent with the podocyte dynamically reacting to the increase in filtration. A second anastomosing branching region draining the glomerular center, which has been termed the interpodocyte space, has fewer restrictions to flow into the final region--the shell-like peripheral urinary space. The physiologic role of the restrictive SPS is yet to be determined but likely possibilities include regulation of glomerular filtration and cleaning of the glomerular filtration barrier.
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Affiliation(s)
- Christopher R Neal
- Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK.
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Kinuno H, Tomoda F, Koike T, Takata M, Inoue H. Effects of uninephrectomy on renal structural properties in spontaneously hypertensive rats*. Clin Exp Pharmacol Physiol 2005; 32:173-8. [PMID: 15743399 DOI: 10.1111/j.1440-1681.2005.04167.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
1. To investigate effects of a reduction in nephron numbers on renal structural properties in hypertension, either unilateral nephrectomy (UNX) or sham operation (SO) was performed at 5 weeks of age in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 9 for each operation for each strain). 2. At 10-12 weeks of age, flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. Kidneys were then perfusion fixed for histological analysis. 3. In the SO groups, the slope of F-P (minimal renal vascular resistance, reflecting overall luminal dimensions of pre- and post-glomerular vasculature) was greater in SHR than in WKY rats. The threshold pressure for beginning filtration at P-GFR (preglomerular to post-glomerular vascular resistance ratio) was higher in SHR than in WKY rats, but the slope of P-GFR (glomerular filtration capacity) did not differ between the two strains. These results suggest that vascular narrowing occurred, especially in the preglomerular resistance vessels in the kidneys of SHR, although glomerular filtration capacity was normal. 4. In UNX animals, the following results were obtained: (i) the slope of F-P was not affected in either strain; (ii) the pressure for beginning filtration at P-GFR was unchanged in WKY rats, but was decreased in SHR; (iii) the slope of P-GFR increased in WKY rats, but a compensatory adaptive increase was missing in SHR; and (iv) histologically, small increases in the luminal cross-sectional area of interlobular arteries and glomerular tuft area were observed in both strains. However, the increase in vascular lumen was more pronounced in SHR, whereas glomerular enlargement was greater in WKY rats. 5. These results suggested that UNX attenuates vascular narrowing of the preglomerular resistance vessels and glomerular structural adaptations to UNX (i.e. increased filtering capacity and glomerular enlargement) are impaired in SHR.
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Affiliation(s)
- Hiroyuki Kinuno
- Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
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19
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Abstract
UNLABELLED Chronic renal diseases that involve proteinuria are typically characterized by an inexorable progression to end-stage renal failure. Many studies suggest that this progression may be the result of factors, such as intraglomerular hypertension and glomerular hypertrophy, that are unrelated to the initial disease. This paper reviews the mechanisms of progression of chronic renal diseases and discusses therapeutic strategies that should prevent or minimize further renal damage and the applicability of these strategies to patients with the rare X-linked lysosomal storage disorder Fabry disease. Renal involvement is a major feature of Fabry disease, which is characterized by vacuolated epithelial cells in the glomerulus and distal tubules, resulting from lipid inclusions within these cells. Although enzyme replacement therapy is the key strategy to halt the progression of Fabry disease, additional therapeutic options include blood pressure control, reduction of proteinuria, lipid control and inhibition of the renin-angiotensin system. CONCLUSION A range of therapeutic options, used in conjunction with enzyme replacement therapy, may have beneficial effects on the renal manifestations of Fabry disease.
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Affiliation(s)
- A Schieppati
- Clinical Research Centre for Rare Diseases, Aldo e Cele Daccò, Ranica, Italy
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James LR, Fantus IG, Goldberg H, Ly H, Scholey JW. Overexpression of GFAT activates PAI-1 promoter in mesangial cells. Am J Physiol Renal Physiol 2000; 279:F718-27. [PMID: 10997922 DOI: 10.1152/ajprenal.2000.279.4.f718] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Effects of hyperglycemia on glomerular cells may be mediated by glucose entry into the hexosamine pathway, and mesangial cell (MC) expression of the hexosamine pathway rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT) is increased in diabetic glomerulosclerosis. We hypothesized that GFAT activity would be an important determinant of gene expression in glomerular MC. When overexpressed in primary MC, GFAT produced a two- to threefold increase in the activity of plasminogen activator inhibitor-1 (PAI-1) promoter. There was a 1.4-fold increase in PAI-1 promoter activity in cells exposed to high glucose (20 mM), whereas in MC overexpressing GFAT, exposure to high glucose caused a 3.5- to 4-fold increase in promoter activity. PAI-1 promoter activation was dependent on GFAT enzyme activity because o-diazoacetyly-L-serine and 6-diazo-5-oxonorleucine, inhibitors of GFAT enzyme activity, abrogated the activation of PAI-1 promoter in MC overexpressing GFAT. Glucosamine, which is downstream of GFAT in the hexosamine pathway, produced a 2.5-fold increase in the PAI-1 promoter activity. In addition to increasing the mRNA levels for transforming growth factor-beta1 (TGF-beta1), GFAT overexpression also increased mRNA levels for the TGF-beta type I and type II receptors. TGF-beta-neutralizing antibody did not normalize PAI-1 promoter activity in MC exposed to glucosamine or those overexpressing GFAT. We conclude that GFAT expression and activity are important determinants of gene expression in MC and that flux through the hexosamine pathway activates expression of genes implicated in vascular injury pathways.
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Affiliation(s)
- L R James
- Division of Nephrology, Department of Medicine, Mount Sinai/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2C4
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21
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Kang MJ, Ingram A, Ly H, Thai K, Scholey JW. Effects of diabetes and hypertension on glomerular transforming growth factor-beta receptor expression. Kidney Int 2000; 58:1677-85. [PMID: 11012901 DOI: 10.1046/j.1523-1755.2000.00328.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Several studies have suggested that transforming growth factor-beta1 (TGF-beta1) is an important determinant of diabetic glomerular injury. TGF-beta1 forms a heteromeric complex with two cellular receptor subtypes, designated TGF-beta RII and TGF-beta RI, but the effects of diabetes mellitus on glomerular TGF-beta receptor expression have not been completely elucidated. We first compared the effect of experimental type I diabetes mellitus and uninephrectomy on glomerular TGF-beta receptor expression in spontaneously hypertensive rats (SHRs), and then sought to determine whether changes in TGF-beta receptor expression were strain specific by studying normotensive Wistar-Kyoto (WKY) rats. METHODS Five groups of male SHRs were studied. The first group received streptozotocin (60 mg/kg IV) and was studied after one week. The second group received streptozotocin and was studied after two weeks. The third group received streptozotocin (60 mg/kg IV) but received insulin to maintain euglycemia. The fourth group of age-matched SHRs served as the control group, while a fifth group of SHRs underwent uninephrectomy. Four groups of male WKY rats were also studied. The first group of WKY rats served as the age-matched control group. The second group of WKY rats received streptozotocin, while a third group of WKY rats underwent uninephrectomy. The fourth group underwent uninephrectomy and received streptozotocin. At each time point, glomeruli were isolated for protein extraction, and the protein was subjected to Western blot analysis of TGF-beta RII and TGF-beta RI expression. RESULTS Basal expression of both TGF-beta receptors per microgram of glomerular protein was similar in normotensive WKY rats and hypertensive SHRs. Hyperglycemia (blood glucose level, 17.8 +/- 2.9 mmol/L) led to an early twofold increase in TGF-beta RII protein expression and a fourfold increase in TGF-beta RI protein expression in the glomeruli of hypertensive diabetic SHRs compared with euglycemic SHRs (blood glucose level, 5.8 +/- 0.8 mmol/L), which was sustained after two weeks. Insulin treatment (blood glucose level, 5. 2 +/- 0.9 mmol/L) normalized both TGF-beta RII and TGF-beta RI expression in the glomeruli of SHRs that received streptozotocin. Glomerular capillary hypertension in the uninephrectomized SHRs led to a twofold increase in glomerular TGF-beta RII protein expression, but did not reproduce the effect of diabetes mellitus on TGF-beta RI expression. In contrast to the findings in SHRs, neither hyperglycemia (blood glucose level, 15.5 +/- 2.1 mmol/L), uninephrectomy, nor hyperglycemia (blood glucose level, 16.8 +/- 3.0 mmol/L) and uninephrectomy altered TGF-beta receptor expression in the glomeruli of normotensive WKY rats. CONCLUSION These studies support the hypothesis that hemodynamic factors and metabolic factors influence glomerular TGF-beta receptor in vivo in the SHRs.
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Affiliation(s)
- M J Kang
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Obata J, Nakamura T, Takano H, Naito A, Kimura H, Yoshida Y, Shimizu F, Guo DF, Inagami T. Increased gene expression of components of the renin-angiotensin system in glomeruli of genetically hypertensive rats. J Hypertens 2000; 18:1247-55. [PMID: 10994756 DOI: 10.1097/00004872-200018090-00011] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The renin-angiotensin system (RAS) is implicated in the development of hypertensive glomerulosclerosis. However, no experimental evidence exists that clearly demonstrates activation of glomerular RAS in hypertensive nephropathy. We used stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether RAS components are increased in glomeruli of SHRSP and whether this increase leads to an increase in mRNA levels for transforming growth factor-beta1 (TGF-beta1). METHODS We examined the sequential changes of urinary albumin excretion (UAE), morphology, and glomerular mRNA expression for TGF-beta1 and fibronectin (FN) in relation to glomerular mRNA expression for angiotensinogen (ATN), angiotensin converting enzyme (ACE), angiotensin II type 1a (AT1a), and type 1b (AT1b) receptors, and intervention with angiotensin II type 1 receptor antagonist candesartan and equihypotensive hydralazine. RESULTS In SHRSP, UAE was normal at 9 weeks of age, but became higher, beginning at 12 weeks of age, than that in the age-matched Wistar-Kyoto (WKY) rats, while SHRSP showed no glomerulosclerosis until 14 weeks of age; it was marked at 24 weeks. Plasma renin activity and plasma angiotensin II level was equivalent in the 9- and 12-week-old SHRSP and the WKY rats; both parameters, however, were elevated in 24-week-old SHRSP as compared with age-matched control. RNase protection assays showed that glomerular levels of ATN, ACE, and AT1a and AT1b receptors mRNA were significantly increased in 9-, 12-, and 14-week-old, but not in 24-week-old SHRSP, compared with age-matched WKY rats. Northern blot analysis showed that glomerular levels of TGF-beta1 and FN mRNA were higher in SHRSP than in WKY rats at all time points. Candesartan reduced UAE to control levels, whereas hydralazine reduced UAE but not to control levels. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis. While candesartan reduced mRNA levels for RAS components, TGF-beta1, and FN to control levels, hydralazine was not effective in this respect. Conclusion Results suggest that increases in glomerular RAS components that occur independently of circulating RAS alter glomerular permselectivity and increase the glomerular expression of TGF-beta1 and FN in young SHRSP. Findings in old SHRSP suggest that altered glomerular permselectivity and an increased glomerular expression of TGF-beta1 and FN may be associated with the activation of systemic RAS.
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MESH Headings
- Albuminuria/genetics
- Albuminuria/physiopathology
- Angiotensin II/blood
- Angiotensinogen/genetics
- Animals
- Antihypertensive Agents/pharmacology
- Benzimidazoles/pharmacology
- Biphenyl Compounds
- Blood Pressure
- Blotting, Northern
- Fibronectins/genetics
- Gene Expression/physiology
- Glomerulosclerosis, Focal Segmental/genetics
- Glomerulosclerosis, Focal Segmental/physiopathology
- Hydralazine/pharmacology
- Hypertension, Renal/drug therapy
- Hypertension, Renal/genetics
- Hypertension, Renal/physiopathology
- Kidney Glomerulus/physiopathology
- Male
- Peptidyl-Dipeptidase A/genetics
- RNA, Messenger/analysis
- Rats
- Rats, Inbred SHR
- Rats, Inbred WKY
- Receptor, Angiotensin, Type 1
- Receptor, Angiotensin, Type 2
- Receptors, Angiotensin/genetics
- Renin/blood
- Renin-Angiotensin System/genetics
- Ribonucleases
- Tetrazoles/pharmacology
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta1
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Affiliation(s)
- J Obata
- Department of Internal Medicine, Yamanashi Medical School, Japan
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23
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Ozen S, Alikasifoglu M, Saatci U, Bakkaloglu A, Besbas N, Kara N, Kocak H, Erbas B, Unsal I, Tuncbilek E. Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am J Kidney Dis 1999; 34:140-5. [PMID: 10401028 DOI: 10.1016/s0272-6386(99)70120-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Polymorphisms of the renin-angiotensin system (RAS) have been shown to affect renal prognosis in a number of diseases. We examined the influence of deletion (D) and insertion (I) polymorphism in the angiotensin I-converting enzyme (ACE) gene and the other polymorphic markers of RAS, and that of plasminogen-activator inhibitor-1 (PAI-1) on renal scarring in reflux nephropathy. Ninety-four children with third- or fourth-degree reflux were the subject of the study. They were stratified into two groups according to the technetium-99m-dimercaptosuccinic acid (DMSA) findings: the first group consisted of 41 patients with no scar formation. In the second group (n = 53), there was significant scar formation in the refluxing units. ACE levels, ACE gene, angiotensin-1 receptor (AT1) A1166C, angiotensinogen (ATG) M235T, and PAI-1 4G/5G polymorphisms were studied. In the second group with scarred kidneys, 18 patients had decreased renal function. The frequency of patients homozygous for the D allele was significantly greater in the second group with scar formation in the refluxing units compared with the first group of patients (P < 0.005). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 4.9-fold risk (P < 0.05, 95% confidence interval). We were unable to find any correlation with the presence ofDD genotype and hypertension, decreased renal function, proteinuria, or sex of the patient. DDgenotype correlated with the serum ACE levels (P < 0.005). AT1and ATGpolymorphisms and PAI-1 polymorphism did not correlate with scar formation or any of the parameters. This study provides evidence that the DDgenotype of ACE may be a genetic susceptibility factor contributing to adverse renal prognosis in reflux nephropathy; namely, scar formation. The role of the synergism between the aforementioned genetic polymorphisms can be enlightened with larger patient groups, possibly through multicenter studies.
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Affiliation(s)
- S Ozen
- Departments of Pediatric Nephrology and Rheumatology, Genetics, Nuclear Medicine, and Clinical Biochemistry, Hacettepe University Faculty of Medicine, Turkey.
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24
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Nakamura T, Obata J, Kimura H, Ohno S, Yoshida Y, Kawachi H, Shimizu F. Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis. Kidney Int 1999; 55:877-89. [PMID: 10027924 DOI: 10.1046/j.1523-1755.1999.055003877.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND The renin-angiotensin system is thought to be involved in the progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) because of the observed renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE inhibition that may help lower blood pressure and preserve glomerular structure. We previously reported a new animal model of progressive glomerulosclerosis induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracellular matrix components. METHODS We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphological lesions in the rat model previously reported. After 10 weeks of treatment with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis index, and the tubulointerstitial lesion index. We performed a semiquantitative evaluation of glomerular immunostaining for TGF-beta and collagen types I and III by immunofluorescence study and of these cortical mRNA levels by Northern blot analysis. RESULTS Untreated rats developed massive proteinuria, renal dysfunction, and severe glomerular and tubulointerstitial injury, whereas uninephrectomized control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive proteinuria, increased creatinine clearance, and ameliorated glomerular and tubulointerstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a renoprotective effect. CONCLUSION These results indicate that ACEIs prevent the progression to ESRF by modulating the effects of Ang II via Ang II type 1 receptor on the production of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.
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Affiliation(s)
- T Nakamura
- Division of Blood Transfusion, Department of Internal Medicine, Niigata University School of Medicine, Niigata, Japan.
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Basile DP. The transforming growth factor beta system in kidney disease and repair: recent progress and future directions. Curr Opin Nephrol Hypertens 1999; 8:21-30. [PMID: 9914857 DOI: 10.1097/00041552-199901000-00005] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Transforming growth factor beta is a multifunctional polypeptide growth factor implicated in a variety of renal diseases. The expression of transforming growth factor beta is enhanced in renal diseases and available evidence suggests that its activity in promoting the synthesis of extracellular matrix plays a crucial role in fibrotic deposition and the decline in renal function. Transforming growth factor beta is, however, also expressed in response to renal injury and may play an important role in normal repair processes. It appears that renal diseases may result from the inappropriate regulation of transforming growth factor beta expression. The determination of the factors that mediate transforming growth factor beta activity will be of primary importance in elucidating the mechanisms leading to renal disease or repair after injury. Both in-vitro and in-vivo studies have demonstrated that proteolytic activity, thrombospondin-1, elevated glucose, angiotensin II, oxidant stress and hemodynamic forces regulate transforming growth factor beta activity through both transcriptional and post-transcriptional mechanisms. In some cases, therapies that may partly disrupt renal transforming growth factor beta activity have shown promise in slowing the progression to end-stage renal disease.
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Affiliation(s)
- D P Basile
- Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA
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Rodríguez-López AM, Flores O, Arévalo MA, López-Novoa JM. Glomerular cell proliferation and apoptosis in uninephrectomized spontaneously hypertensive rats. KIDNEY INTERNATIONAL. SUPPLEMENT 1998; 68:S36-40. [PMID: 9839281 DOI: 10.1046/j.1523-1755.1998.06810.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
We studied renal function, glomerular cell proliferation and apoptosis for three months after uninephrectomy (UNX) in young, male, spontaneously hypertensive rats (SHR). Apoptosis was assessed by in situ dUTP biotin nick-end labeling method (TUNEL) and by propidium iodide staining. Proliferation rate was determined by immunohistochemistry to proliferating cell nuclear antigen (PCNA). Glomerular bcl-2 expression was assessed by Northern blot analysis. Our results indicate a parallel increase in proliferation and in apoptotic rates in glomerular cells from the first to the second month after UNX. In the third month after UNX, PCNA-labeled cell number continues increasing, whereas TUNEL-labeled cells did not increase. Bcl-2 expression was negative in the first and second months and increased in the third month. Glomerular size and proteinuria increased progressively along the three months of follow-up. Our observations demonstrate a different profile of cell proliferation and apoptosis during the genesis of early glomerular damage in UNX-SHR.
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Affiliation(s)
- A M Rodríguez-López
- Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Salamanca, Spain
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27
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Luño J, Garcia de Vinuesa S, Gomez-Campdera F, Lorenzo I, Valderrábano F. Effects of antihypertensive therapy on progression of diabetic nephropathy. KIDNEY INTERNATIONAL. SUPPLEMENT 1998; 68:S112-9. [PMID: 9839294 DOI: 10.1046/j.1523-1755.1998.06823.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
There is a clear relationship between hypertension and the microvascular complications of diabetes. Genetic predisposition to hypertension has been correlated to the risk of diabetic nephropathy in type I diabetes, and hypertension is a well known risk factor for developing nephropathy in patients with type II diabetes. Multiple studies have emphasized the importance of hypertension on renal disease progression, and blood pressure control with conventional antihypertensive drugs slows the rate of renal function loss in diabetic nephropathy. Furthermore, evidence of the role of renin-angiotensin system (RAS) on progression of renal damage has focused much interest on the therapeutic action of the RAS blockade. In patients with type I diabetes, blocking the RAS with angiotensin converting enzyme (ACE) inhibitors prevents progression from microalbuminuria to overt nephropathy, and in overt nephropathy decreases the gradual loss of renal function beyond its blood pressure lowering effect. Less clinical information is available in type II diabetic nephropathy, but our experience and some recent studies suggest that ACE inhibitors also have a renoprotective action in type II diabetes. The role of calcium channel blockers in diabetic nephropathy is not clear. Several short-term studies with the first generation dihydropyridine calcium antagonists showed a lower effect on urinary albumin excretion and a more rapid progression to renal failure than with ACE inhibitors. However, other calcium channel blockers, particularly of the non-dihydropyridine type, have been shown to have a beneficial effect on diabetic nephropathy, decreasing proteinuria and slowing progression.
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Affiliation(s)
- J Luño
- Servicio de Nefrologia, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
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28
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Bürger A, Wagner C, Viedt C, Reis B, Hug F, Hänsch GM. Fibronectin synthesis by human tubular epithelial cells in culture: effects of PDGF and TGF-beta on synthesis and splicing. Kidney Int 1998; 54:407-15. [PMID: 9690207 DOI: 10.1046/j.1523-1755.1998.00009.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Enhanced synthesis of extracellular matrix proteins including fibronectin (FN) is associated with the development of sclerosis. In this context we studied FN synthesis by tubular epithelial cells in response to transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF). METHODS FN protein synthesis by human tubular epithelial cells in culture (TEC) was measured by biosynthetic labeling and ELISA. Splicing of FN was assessed by RT-PCR and by Northern blotting. RESULTS Cultivated TEC synthesized and released FN, the majority of which was deposited as an unsoluble protein and a minor portion (10 to 15%) was released into the supernatant. TGF-beta and, to a lesser degree, PDGF, up-regulated FN synthesis. All three FN splice variants (EDA, EDB, and IIICS) were produced. PDGF did not influence the splicing. TGF-beta preferentially up-regulated the EDA splice variant, but had no effect on the splicing of the other domains. CONCLUSIONS PDGF and TGF-beta both up-regulate FN synthesis of TEC. TGF-beta, but not PDGF, also changed the quality of the de novo synthesized FN, and thus has a different role in the development of sclerosis.
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Affiliation(s)
- A Bürger
- Institut für Immunologie, Medzinische Klinik, Universität Heidelberg, Germany
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29
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Franco M, Paniagua R, Herrera-Acosta J. Renal effects of renin-angiotensin system blockade. Curr Opin Nephrol Hypertens 1998; 7:153-8. [PMID: 9529617 DOI: 10.1097/00041552-199803000-00003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pharmacological interruption of the renin-angiotensin system at different pathway levels has extended our knowledge on the distribution of angiotensin receptors in different nephron segments, its regulation and tubular cell responses. Novel beneficial effects obtained with blockade of this peptide on cellular proliferation and its interaction with other vasoactive systems are particularly important for preventing renal damage.
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Affiliation(s)
- M Franco
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
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30
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Abstract
Angiotensin II (Ang II) blockade and restriction of dietary protein are thought to retard progression of renal disease primarily by reducing glomerular capillary pressure and thereby reducing injury to renal tissues. Relatively recent data suggest that both of these therapies may also act through pressure-independent mechanisms to reduce repair processes that follow tissue injury and which, if not self-limited, can continue to cause tissue fibrosis and organ failure. We review recent data suggesting that Ang II is a profibrotic molecule independent of blood pressure. Therapeutic actions of dietary restriction of total protein and restriction of the amino acid L-arginine that appear independent of pressure are also discussed. These effects are separated into those that reduce injury and those that reduce tissue repair. Finally, we ask whether the Ang II blockade or restriction of dietary protein could be more effective if they were aimed not only at limiting injury, but also at halting excessive repair.
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Affiliation(s)
- H Peters
- Division of Nephrology, University of Utah School of Medicine, Salt Lake City, USA
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31
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Kagami S, Kuhara T, Okada K, Kuroda Y, Border WA, Noble NA. Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells. Kidney Int 1997; 51:664-71. [PMID: 9067897 DOI: 10.1038/ki.1997.96] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Previous studies indicate that angiotensin II (Ang II) stimulates extracellular matrix synthesis through induction of transforming growth factor-beta (TGF-beta) expression. Here we investigate Ang II effects on the plasmin protease system. Plasmin both degrades extracellular matrix itself and activates metalloproteinases which then degrade collagens. Plasmin production is determined by the balance between plasminogen activators (PA) and their inhibitors (PAI-1,2). The data presented here indicate that Ang II treatment of mesangial cells in culture markedly increases PAI-1 gene transcription and PAI-1 mRNA levels but does not change the half life of PAI-1 mRNA. Increased PAI-1 protein was detected 24 hours after Ang II stimulation with a concomitant decrease of PA activity. To determine whether these effects were mediated by TGF-beta, cells were coincubated with Ang II and neutralizing antibody to TGF-beta. Induction of PAI-1 at four hours was not altered but the prolonged effect of Ang II on PAI-1 protein synthesis was markedly diminished. Thus, Ang II acts both through rapid, direct transcriptional up-regulation of the PAI-1 gene and through induction of TGF-beta, providing sustained changes in the PAI-1/PA system, which would favor extracellular matrix accumulation by inhibiting turnover. These data provide further evidence that Ang II can act as a potent fibrogenic molecule independent of its effects on blood pressure.
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Affiliation(s)
- S Kagami
- Department of Pediatrics, School of Medicine, University of Tokushima, Japan
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Azuma H, Nadeau K, Mackenzie HS, Brenner BM, Tilney NL. Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft. Transplantation 1997; 63:519-28. [PMID: 9047144 DOI: 10.1097/00007890-199702270-00006] [Citation(s) in RCA: 101] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Functioning nephron mass has recently been implicated as a risk factor for development of chronic "rejection" of kidney allografts. Reductions in nephron number below 50% may induce glomerular hypertension and hyperfiltration in surviving units, which in turn lead to graft injury. In the present study, which extends and amplifies our previous investigations, cellular and molecular characteristics of single allografts from F344 donors in bilaterally nephrectomized LEW recipients, our standard experimental model of chronic renal allograft dysfunction, were compared with allografts from recipients where total renal mass was reduced (by ligating branches of the graft renal artery) or restored to normal levels by transplanting or retaining a second kidney. Our findings in this study confirm that progressive proteinuria and structural injury in recipients of single allografts were accentuated in grafts with reduced mass but virtually absent in rats with increased kidney mass. A striking observation was that patterns of cell surface molecule expression, cellular infiltration, and expression of all T cell- and macrophage-associated products studied were all markedly modulated by changes in renal mass. Moreover, several molecules that are up-regulated before evidence of graft injury are down-regulated by providing increased renal mass. These data show that the quantity of functioning renal mass is not only an important independent determinant of the tempo and intensity of chronic renal allograft failure, but also a potent modulator of fundamental cellular and molecular components of a complex process. This phenomenon involves antigen-dependent and antigen-independent elements that ultimately result in chronic allograft failure.
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Affiliation(s)
- H Azuma
- Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts, USA
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33
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Abstract
Locally produced cytokines and growth factors may mediate tissue remodelling processes, as observed in renal transplants exposed to ischemia or acute rejection episodes. The present study was designed to investigate mRNA transcript levels of platelet-derived growth factor (PDGF)-receptor beta, PDGF-A, PDGF-B, fibroblast growth factor-1, and transforming growth factor beta 1 in normal rat kidneys, in kidneys following contralateral nephrectomy and in renal transplants with acute or chronic rejection. Platelet-derived growth factor-receptor beta mRNA levels increased significantly in syngeneic and allogeneic transplants in the first week after transplantation and in allogeneic transplants with chronic rejection. Immunohistochemistry showed induction of PDGF-receptor beta protein expression on vascular wall cells in such grafts. Platelet-derived growth factor-A chain mRNA levels increased in day 3 allografts and in syngeneic LEW grafts, while PDGF-B chain mRNA levels showed no significant changes with transplantation. Fibroblast growth factor-1 mRNA levels were detectable in normal kidneys, tended to decrease with acute rejection, and increased significantly in chronic rejection. Transforming growth factor-beta 1 transcripts increased in acute and chronic rejection; immunohistochemistry showed predominantly glomerular localization of the transforming growth factor-beta 1 protein. We conclude that transplantation and rejection are associated with changes in the intragraft mRNA levels for several growth factors; chronic rejection is characterized by an increase in fibroblast growth factor-1 and transforming growth factor-beta 1 transcript levels.
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Affiliation(s)
- L C Paul
- Department of Medicine, University of Toronto at St Michael's Hospital, Ontario, Canada
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Shankland SJ, Pippin J, Pichler RH, Gordon KL, Friedman S, Gold LI, Johnson RJ, Couser WG. Differential expression of transforming growth factor-beta isoforms and receptors in experimental membranous nephropathy. Kidney Int 1996; 50:116-24. [PMID: 8807580 DOI: 10.1038/ki.1996.294] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In membranous nephropathy (MN) overproduction of matrix by glomerular epithelial cells (GEC) is believed to be responsible for glomerular basement membrane thickening and spikes. We studied experimental MN in rats (passive Heymann nephritis, PHN) at 5, 10 and 30 days. PHN rats exhibited a marked increase in GEC immunostaining for TGF-beta 2 at all time points. TGF-beta 3 staining was increased at day 10 only, and TGF-beta 1 was unchanged. Glomerular mRNA for TGF-beta 2 and -beta 3 was increased by day 5 when urine protein increased, whereas TGF-beta 1 was not. TGF-beta 2 bioactivity was increased at day 5. There was also a marked increase in GEC immunostaining for TGF-beta receptor type I (T beta IR) and TGF-beta receptor type II (T beta IIR) at all time points in PHN. mRNA levels for both receptors increased at day 5. Increases in protein expression and mRNA levels for the TGF-beta 2 and -beta 3 isoforms, and T beta IR and T beta RII were prevented by complement depletion. We conclude that complement-mediated injury to the GEC in vivo is associated with the up-regulation of TGF-beta 2 and -beta 3 isoforms, an increase in TGF-beta 2 bioactivity, and an increase in T beta RI and T beta RII expression. This contrasts with changes in TGF-beta 1 reported in mesangial disease, suggesting that TGF-beta 2 and -beta 3 may be important in diseases of the GEC. The differential expression of TGF-beta isoforms and receptors may be important determinants of the GEC response to injury.
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Affiliation(s)
- S J Shankland
- Division of Nephrology, University of Washington, Seattle, USA
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Ingram A, Parbtani A, Thai K, Ly H, Shankland SJ, Morrissey G, Scholey JW. Dietary supplementation with L-arginine limits cell proliferation in the remnant glomerulus. Kidney Int 1995; 48:1857-65. [PMID: 8587245 DOI: 10.1038/ki.1995.484] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
One effect of L-arginine is to increase nitric oxide (NO) production by endothelial cells. NO directly reduces endothelin-1 production by endothelial cells and also inhibits platelet-derived growth factor (PDGF) induced cell proliferation. Since subtotal renal ablation is associated with an early phase of cell proliferation in the glomerulus that precedes injury, we examined the effect of dietary supplementation with L-arginine on glomerular cell proliferation and expression of the cytokine endothelin-1 (ET-1). A first group of renal-ablated rats was untreated. A second group of renal-ablated rats received L-arginine (1%) in the drinking water. Two weeks after subtotal ablation renal cortical tissue was snap frozen for immunohistochemical analysis for proliferating cell nuclear antigen (PCNA) expression and ET-1. Protein and total RNA was extracted from sieved glomeruli. mRNA levels were quantitated by co-amplification RT-PCR utilizing specific 5' and 3' primers for rat ET-1 and beta-actin. L-arginine reduced the number of PCNA positive nuclei in remnant glomeruli, and Western blot Analysis of glomerular proteins also showed that L-arginine reduced PCNA expression. Glomerular ET-1 mRNA levels and protein immunostaining declined in the rats receiving L-arginine. We conclude that dietary supplementation with L-arginine reduces early cell proliferation in the remnant glomerulus, an effect that may be mediated, in part, by a decrease in ET-1 production.
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Affiliation(s)
- A Ingram
- Department of Medicine, University of Toronto, Ontario, Canada
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