AI Article Synopsis
- Diabetic nephropathy (DN) is a major complication of diabetes leading to kidney failure, and the role of insulin-like growth factor (IGF) signaling in DN is not well understood.
- The study found that PAPP-A (a protein that activates IGF) and its inhibitors (STC1 and STC2) are present in human kidneys and that an increase in active PAPP-A is linked to DN severity.
- Targeting PAPP-A activity could be a potential new treatment approach for DN, as it appears that balance between PAPP-A and STCs is critical for kidney health.
Article 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.
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| http://dx.doi.org/10.1016/j.metabol.2022.155218 | DOI Listing |
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