title: FK506 reduces albuminuria through improving podocyte nephrin and podocin expression in diabetic rats.
abstract: OBJECTIVE
  Several works in the setting of early experimental diabetic nephropathy using anti-inflammatory drugs, such as the calcineurin inhibitor FK506, have shown prevention of the development or amelioration of renal injury including proteinuria. The exact mechanisms by which anti-inflammatory drugs lower the albuminuria have not been still clarified well.
  
  
  METHODS
  The diabetic rats were induced by using streptozotocin.
  
  
  METHODS
  The diabetic rats were subjected to oral FK506 treatment at a dose of 0.5 or 1.0 mg/kg daily for 4 weeks.
  
  
  METHODS
  Renal histology for the ultrastructural evaluation was determined by electron microscope, followed by analyses of renal nephrin and podocin and detection of renal iNOS(+) macrophages and NF-κB-p-p65(+).
  
  
  RESULTS
  Elevated 24-h urinary albumin excretion rate was markedly attenuated by FK506 treatment. In diabetic model rats, FK506 treatment at a dose of 0.5 or 1.0 mg/kg significantly increased the expression of nephrin and podocin when compared to control. As expected, rats in control diabetic group had an increase in GBM thickening and foot process effacement when compared to normal rats; increased GBM thickening and foot process effacement were ameliorated by FK506 treatment with 0.5 and 1.0 mg/kg. Histologically, there was marked accumulation of ED-1(+)cells (macrophages) in diabetic kidneys, and FK506 treatment failed to inhibit it. In contrast, FK506 treatment at 0.5 and 1.0 mg/kg doses significantly inhibited the elevated ED-1(+)/iNOS(+) cells in the kidneys of diabetic rats. ED-1(+)/NF-κB-p-p65(+) cells were significantly increased in positive diabetic kidneys compared to those of normal rats. FK506 treatment at 0.5 and 1.0 mg/kg significantly attenuated the elevated ED-1(+)/NF-κB-p-p65(+) cells in diabetic kidneys. Additionally, a positive correlation was observed between ED-1(+)/iNOS(+) cells and albuminuria (r = 0.87, p < 0.05). Likewise, ED-1(+)/iNOS(+) cells were correlated negatively with both nephrin and podocin protein (r = -0.70, p < 0.05; r = -0.68, p < 0.05, respectively).
  
  
  CONCLUSIONS
  Our results show that FK506 not only upregulates expression of nephrin and podocin but also inhibits macrophage activation to protect against podocyte injury.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Qi
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
authors.forename: X-X
authors.initials: XX
authors.lastname: Xu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. wuyonggui@medmail.com.cn.
authors.forename: Y-G
authors.initials: YG
authors.lastname: Wu
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D065095:Calcineurin Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D046529:Microscopy, Electron, Transmission; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C113267:nephrin; D016559:Tacrolimus
keywords: Diabetic nephropathy; FK506; Macrophage; Nephrin; Podocin; Podocytes