BACKGROUND: Recent disclosure of podocyte proteins has unraveled previously rather mysterious mechanisms that govern glomerular perm-selectivity in health and disease. Here we addressed the role of nephrin, CD2-associated protein (CD2AP), and podocin together with the integrity of the slit diaphragm in the pathogenesis of proteinuria of patients with diabetes and nephropathy. METHODS: Nephrin mRNA and protein expression were evaluated in parallel in adult diabetic patients by in situ hybridization and immunohistochemistry. For comparison, nondiabetic patients with minimal change nephrosis and normal control patients were evaluated. CD2AP and podocin expression by immunohistochemistry was also assessed. The filtration slit was analyzed by morphometry and transmission electron microscopy. RESULTS: Extracellular nephrin mRNA and protein were markedly reduced in diabetic patients. No changes were found in patients with minimal change versus controls. CD2AP and podocin were comparable in all subjects. Ultrastructural analysis showed in diabetic patients a remarkable reduction in the percentage of electron dense slit diaphragms, despite a frequency of the filtration slits comparable to control patients. CONCLUSION: Down-regulation of nephrin and loss of the electron dense structure of slit diaphragm indicate a novel mechanism accounting for proteinuria in diabetic nephropathy. To the extent that glomerular protein trafficking contributes to renal disease progression, our findings may have clinical relevance. Reduction of nephrin in the context of normal expression of CD2AP and podocin can be taken reasonably as a specific marker of renal disease in diabetes. Therapies targeted at correcting podocyte nephrin might be of value for diabetic medicine.
BACKGROUND: Recent disclosure of podocyte proteins has unraveled previously rather mysterious mechanisms that govern glomerular perm-selectivity in health and disease. Here we addressed the role of nephrin, CD2-associated protein (CD2AP), and podocin together with the integrity of the slit diaphragm in the pathogenesis of proteinuria of patients with diabetes and nephropathy. METHODS:Nephrin mRNA and protein expression were evaluated in parallel in adult diabeticpatients by in situ hybridization and immunohistochemistry. For comparison, nondiabeticpatients with minimal change nephrosis and normal control patients were evaluated. CD2AP and podocin expression by immunohistochemistry was also assessed. The filtration slit was analyzed by morphometry and transmission electron microscopy. RESULTS: Extracellular nephrin mRNA and protein were markedly reduced in diabeticpatients. No changes were found in patients with minimal change versus controls. CD2AP and podocin were comparable in all subjects. Ultrastructural analysis showed in diabeticpatients a remarkable reduction in the percentage of electron dense slit diaphragms, despite a frequency of the filtration slits comparable to control patients. CONCLUSION: Down-regulation of nephrin and loss of the electron dense structure of slit diaphragm indicate a novel mechanism accounting for proteinuria in diabetic nephropathy. To the extent that glomerular protein trafficking contributes to renal disease progression, our findings may have clinical relevance. Reduction of nephrin in the context of normal expression of CD2AP and podocin can be taken reasonably as a specific marker of renal disease in diabetes. Therapies targeted at correcting podocyte nephrin might be of value for diabetic medicine.
Authors: Akihiro Fukuda; Larysa T Wickman; Madhusudan P Venkatareddy; Yuji Sato; Mahboob A Chowdhury; Su Q Wang; Kerby A Shedden; Robert C Dysko; Jocelyn E Wiggins; Roger C Wiggins Journal: Kidney Int Date: 2011-09-21 Impact factor: 10.612
Authors: Elena Gagliardini; Sara Conti; Ariela Benigni; Giuseppe Remuzzi; Andrea Remuzzi Journal: J Am Soc Nephrol Date: 2010-10-28 Impact factor: 10.121
Authors: Alaa S Awad; Michael Rouse; Lixia Liu; Amy L Vergis; Diane L Rosin; Joel Linden; John R Sedor; Mark D Okusa Journal: J Am Soc Nephrol Date: 2007-11-28 Impact factor: 10.121
Authors: Eugenel B Espiritu; Huajun Jiang; Sophie Moreau-Marquis; Mara Sullivan; Kunimasa Yan; Donna Beer Stolz; Matthew G Sampson; Neil A Hukriede; Agnieszka Swiatecka-Urban Journal: J Biol Chem Date: 2019-05-31 Impact factor: 5.157