Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy

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  • Jessica R Mader, Cellular and Molecular Immunology Research Centre, United Kingdom
  • Zachary T Resch, Cellular and Molecular Immunology Research Centre, United Kingdom
  • Gary R McLean, Cellular and Molecular Immunology Research Centre, United Kingdom
  • Jakob Hauge Mikkelsen
  • Claus Oxvig
  • Ronald J Marler, Endocrine Research Unit, Division of Endocrinology, Mayo Clinic , United States
  • Cheryl A. Conover, Institut for Kemi og Bioteknologi, Denmark
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.
Original languageEnglish
JournalJournal of Endocrinology
Pages (from-to)51-58
Number of pages8
Publication statusPublished - 1 Oct 2013

    Research areas

  • Aging, Animals, Bowman Capsule, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Female, Glomerular Mesangium, Humans, Kidney, Kidney Glomerulus, Mice, Mice, Knockout, Pregnancy, Pregnancy-Associated Plasma Protein-A

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