title: Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy.
abstract: We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Mader
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Resch
authors.forename: Gary R
authors.initials: GR
authors.lastname: McLean
authors.forename: Jakob H
authors.initials: JH
authors.lastname: Mikkelsen
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Marler
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D050476:Bowman Capsule / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005920:Glomerular Mesangium / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000172:deficiency*
chemical_list: D011266:Pregnancy-Associated Plasma Protein-A
keywords: Bowman's capsule; diabetes; kidney; pregnancy-associated plasma protein-A