Increased activity of the metalloproteinase PAPP-A promotes diabetes-induced glomerular hypertrophy

Malene R. Jepsen, Jakob A. Østergaard, Cheryl A. Conover, Lise Wogensen, Henrik Birn, Søren P. Krag, Robert A. Fenton, Claus Oxvig

Research output: Contribution to journalArticlepeer-review


Background: Diabetic nephropathy (DN) is a serious complication of diabetes and a common cause of end stage renal failure. Insulin-like growth factor (IGF)-signaling has been implicated in DN, but is mechanistically poorly understood. Here, we assessed the activity of the metalloproteinase PAPP-A, an activator of IGF activity, and its possible interaction with the endogenous PAPP-A inhibitors stanniocalcin (STC)-1 and -2 in the mammalian kidney under normal and hyperglycemic conditions. Methods and results: Immunohistochemistry demonstrated that PAPP-A, its proteolytic substrate IGF binding protein-4, STC1 and STC2 are present in the human kidney. Endogenous inhibited complexes of PAPP-A (PAPP-A:STC1 and PAPP-A:STC2) were demonstrated in media conditioned by human mesangial cells (HMCs), suggesting that PAPP-A activity is regulated by the STCs in kidney tissue. A method for the selective detection of active PAPP-A in tissue was developed and a significant increase in glomerular active PAPP-A in human diabetic kidney relative to normal was observed. In DN patients, the estimated glomerular filtration rate correlated with PAPP-A activity. In diabetic mice, glomerular growth was reduced when PAPP-A activity was antagonized by adeno-associated virus-mediated overexpression of STC2. Conclusion: We propose that PAPP-A activity in renal tissue is precisely balanced by STC1 and STC2. An imbalance in this equilibrium causing increased PAPP-A enzymatic activity potentially contributes to the development of DN, and thus, therapeutic targeting of PAPP-A activity may represent a novel strategy for its treatment.

Original languageEnglish (US)
Article number155218
JournalMetabolism: Clinical and Experimental
StatePublished - Jul 2022


  • Diabetic nephropathy
  • Insulin-like growth factor-1 (IGF-1)
  • Pregnancy-associated plasma protein-A (PAPP-A)
  • Stanniocalcin-2 (STC2)
  • Transforming growth factor-β (TGF-β)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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