title: Renal accumulation of pentosidine in non-diabetic proteinuria-induced renal damage in rats.
abstract: BACKGROUND
  Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking.
  
  
  METHODS
  Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry.
  
  
  RESULTS
  Renal pentosidine was elevated in untreated AN (0.14+/-0.04 micromol/mol valine) vs healthy controls (0.04+/-0.01 micromol/mol valine, P<0.01). In lisinopril-treated AN, pentosidine was lower (0.09+/-0.02 micromol/mol valine) than in untreated AN (P<0.05). In unilateral proteinuria, pentosidine was similar in non-proteinuric and proteinuric kidneys. After 30 weeks of unilateral proteinuria, pentosidine was increased in both kidneys (0.26+/-0.10 micromol/mol valine) compared with controls (0.18+/-0.06 micromol/mol valine, P<0.05). Pentosidine (AN, week 30) was also increased compared with AN at week 12 (0.16+/-0.06 micromol/mol valine, P<0.01). In control and diseased kidneys, pentosidine was present in the collecting ducts. In proteinuric kidneys, in addition, pentosidine was present in the brush border and cytoplasm of dilated tubular structures, i.e. at sites of proteinuria-induced tubular damage.
  
  
  CONCLUSIONS
  Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE accumulation, supporting a relationship between abnormal renal protein trafficking, proteinuria-induced tubular damage and tubular pentosidine accumulation. Future studies, applying specific AGE inhibitors, should be conducted to provide insight into the pathophysiological significance of renal AGEs in non-diabetic renal disease.
authors.affiliation: University Medical Center Groningen, Department of Nephrology, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Waanders
authors.forename: Wendela L
authors.initials: WL
authors.lastname: Greven
authors.forename: John W
authors.initials: JW
authors.lastname: Baynes
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Thorpe
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Kramer
authors.forename: Ryoji
authors.initials: R
authors.lastname: Nagai
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sakata
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001794:Blood Pressure; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000652:urine; D004317:Doxorubicin / Q000633:toxicity; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D004317:Doxorubicin; D001120:Arginine; D002784:Cholesterol; D003404:Creatinine; C062187:pentosidine; D017706:Lisinopril; D008239:Lysine