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

• Published in: Metabolism, clinical and experimental clinical and experimental, 2022-07, Vol.132, p.155218-155218, Article 155218
• Main Authors: Jepsen, Malene R., Østergaard, Jakob A., Conover, Cheryl A., Wogensen, Lise, Birn, Henrik, Krag, Søren P., Fenton, Robert A., Oxvig, Claus
• Format: Article
• Language: English
• Subjects: 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)
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2022.155218

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. 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. 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. [Display omitted] •A novel method for measurement of PAPP-A proteolytic activity in situ is presented.•Human diabetic nephropathy is associated with increased glomerular PAPP-A activity.•IGF-promoting PAPP-A activity is regulated by endogenous STC1 and STC2 in human kidney.•Overexpression of STC2 in mice reduces diabetes-induced glomerular growth.