Proteinuria and Glomerular Damage in Rab3A Knockout Mice Chronically Fed a High-Glucose Diet

作者：Armelloni Silvia; Calvaresi Novella; Ikehata Masami; Corbelli Alessandro; Mattinzoli Deborah; Giardino Laura A; Li Min; Messa Piergiorgio; Rastaldi Maria P^*

来源：Nephron Experimental Nephrology, 2012, 120(2): E69-E80.

DOI：10.1159/000336166

• High glucose
• Glomerular damage
• Proteinuria
• Podocyte
• Rab3A
• Actin

Background/Aims: The relative contribution of genetic factors and dietary patterns to glomerular damage in healthy individuals and prediabetic conditions is currently unclear. All Rab3A knockout (KO) mice spontaneously develop macroalbuminuria, but only male mice exhibit a glucose-intolerant phenotype, thus making the model suitable to examine the impact of a diet on preexisting podocyte damage. Methods: Male and female Rab3A KO and wild-type (WT) mice were chronically fed a high-glucose diet (HGD). Biochemical tests, histology and immunohistochemistry were periodically performed whilst primary podocytes served for in vitro analyses. Results: Chronic administration of an HGD did not induce de novo alterations in WT kidneys but caused progressive worsening of podocyte and glomerular damage in both male and female Rab3A KO. Though glomerular lesions, reminiscent of human diabetic nephropathy, were more severe in male mice, overt proteinuria and renal damage were also evident in female mice. The in vitro analysis of Rab3A WT and KO podocytes revealed diminished actin plasticity in the cell processes of KO podocytes. Furthermore, a modest increase in glucose concentration induced profound cytoskeletal changes only in Rab3A KO cells. Conclusions: Our data show that chronic administration of an HGD to Rab3A KO mice that have a genetic defect that impairs podocyte actin plasticity results in increased podocyte damage and leads to overt proteinuria. If the same diet is given to male Rab3A KO animals, with additionally altered glucose homeostasis, this results in renal lesions similar to those of human diabetic nephropathy.

• 出版日期2012