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

Abstract

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.

• Authors: Malene R Jepsen, Jakob A Østergaard, Cheryl A Conover, Lise Wogensen, Henrik Birn, Søren P Krag, Robert A Fenton, Claus Oxvig
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 132 Pg. 155218 (07 2022) ISSN: 1532-8600 [Electronic] United States
• PMID: 35588861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Intercellular Signaling Peptides and Proteins
• Pregnancy-Associated Plasma Protein-A

Topics

• Animals
• Diabetes Mellitus, Experimental (complications)
• Diabetic Nephropathies (etiology)
• Humans
• Hypertrophy
• Intercellular Signaling Peptides and Proteins (metabolism)
• Mammals (metabolism)
• Mice
• Pregnancy-Associated Plasma Protein-A (metabolism)
• Proteolysis