Nephrin Expression Is Reduced in Human Diabetic Nephropathy

TLDR

The study quantified nephrin distribution in renal biopsies from 17 diabetic nephrotic patients, 6 diabetic microalbuminuric patients, and 10 controls using digital image analysis, and performed in vitro podocyte experiments showing that glycated albumin and angiotensin II suppress nephrin expression. Nephrin staining was markedly reduced (≈65–67 %) and shifted from punctate/linear to granular in diabetic nephrotic patients, with similar reductions in microalbuminuric patients, and the in vitro data indicate that glycated albumin via RAGE and angiotensin II via cytoskeletal changes drive this early downregulation.

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.