Nephrin Expression Is Reduced in Human Diabetic Nephropathy
Evidence for a Distinct Role for Glycated Albumin and Angiotensin II
- Sophie Doublier1,
- Gennaro Salvidio2,
- Enrico Lupia1,
- Vesa Ruotsalainen3,
- Daniela Verzola2,
- Giacomo Deferrari2 and
- Giovanni Camussi1
- 1Department of Internal Medicine, University of Turin, Center for Experimental Research and Medical Sciences (CERMS), Turin, Italy
- 2Department of Internal Medicine, University of Genoa, Genoa, Italy
- 3Department of Biochemistry, University of Oulu, Oulu, Finland
Abstract
We studied the distribution of nephrin in renal biopsies from 17 patients with diabetes and nephrotic syndrome (7 type 1 and 10 type 2 diabetes), 6 patients with diabetes and microalbuminuria (1 type 1 and 5 type 2 diabetes), and 10 normal subjects. Nephrin expression was semiquantitatively evaluated by measuring immunofluorescence intensity by digital image analysis. We found an extensive reduction of nephrin staining in both type 1 (67 ± 9%; P < 0.001) and type 2 (65 ± 10%; P < 0.001) diabetic patients with diabetes and nephrotic syndrome when compared with control subjects. The pattern of staining shifted from punctate/linear distribution to granular. In patients with microalbuminuria, the staining pattern of nephrin also showed granular distribution and reduction intensity of 69% in the patient with type 1 diabetes and of 62 ± 4% (P < 0.001) in the patients with type 2 diabetes. In vitro studies on human cultured podocytes demonstrated that glycated albumin and angiotensin II reduced nephrin expression. Glycated albumin inhibited nephrin synthesis through the engagement of receptor for advanced glycation end products, whereas angiotensin II acted on cytoskeleton redistribution, inducing the shedding of nephrin. This study indicates that the alteration in nephrin expression is an early event in proteinuric patients with diabetes and suggests that glycated albumin and angiotensin II contribute to nephrin downregulation.
Footnotes
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Address correspondence and reprint requests to Dr. G. Camussi, Cattedra di Nefrologia, Dipartimento di Medicina Interna, Ospedale Maggiore S. Giovanni Battista, Corso Dogliotti 14, 10126, Torino, Italy. E-mail: giovanni.camussi{at}unito.it.
Received for publication 16 September 2002 and accepted in revised form 2 January 2003.
Ang II, angiotensin II; DN, diabetic nephropathy; GA, glycated albumin; GAPDH, glyceraldehyde phosphate dehydrogenase; GEC, glomerular epithelial cell; GN, glomerulonephritis; IF, immunofluorescence; mAb, monoclonal antibody; RAGE, receptor for advanced glycation end products; RAS, renin-angiotensin system.
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