Anna Levin1, Angelina Schwarz1, Jenny Hulkko1, Liqun He2, Ying Sun2, Peter Barany1, Annette Bruchfeld1,3, Maria Herthelius4, Lars Wennberg5, Kerstin Ebefors6, Jaakko Patrakka7, Christer Betsholtz2, Jenny Nyström6, Johan Mölne8, Kjell Hultenby7, Anna Witasp1, Annika Wernerson1. 1. Department of Clinical Science, Intervention and Technology, Divison of Renal Medicine Karolinska Institutet, Stockholm, Sweden. 2. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 3. Department of Health, Medicine and Caring Sciences, Linköpings universitet Hälsouniversitetet, Linkoping, Sweden. 4. Department of Clinical Science, Intervention, and Technology, Division of Pediatrics, Karolinska Institutet, StockholmSweden. 5. Department of Clinical Science, Intervention and Technology, Division of Transplantation Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 6. Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 7. Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. 8. Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
Abstract
BACKGROUND: IgA nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV. METHODS: Glomerular gene expression was measured using microarrays on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IFL) staining (IgAN patients; n = 4 and nephrectomized kidneys; n = 3) and semi-quantitatively by immunogold electron microscopy (IgAN/IgAV patients; n = 21, MN; n = 5 and living kidney donors; n = 6). Histopathological grading was performed according to Oxford and Banff classifications. Clinical data was collected at the time of biopsy and follow-up. RESULTS: Dendrin mRNA levels were higher (p = 0.01) in IgA patients compared to MN patients and controls, and most prominently in patients with preserved kidney function and less chronic histopathological changes. Whereas IFL staining did not differ between groups, iEM revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with slower annual progression rate and milder histopathological changes. CONCLUSION: Dendrin mRNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.
BACKGROUND: IgA nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV. METHODS: Glomerular gene expression was measured using microarrays on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IFL) staining (IgAN patients; n = 4 and nephrectomized kidneys; n = 3) and semi-quantitatively by immunogold electron microscopy (IgAN/IgAV patients; n = 21, MN; n = 5 and living kidney donors; n = 6). Histopathological grading was performed according to Oxford and Banff classifications. Clinical data was collected at the time of biopsy and follow-up. RESULTS: Dendrin mRNA levels were higher (p = 0.01) in IgA patients compared to MN patients and controls, and most prominently in patients with preserved kidney function and less chronic histopathological changes. Whereas IFL staining did not differ between groups, iEM revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with slower annual progression rate and milder histopathological changes. CONCLUSION: Dendrin mRNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.