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Abstract: TH-PO423

The Loss of Peroxidasin Causes a Sex-Dependent Susceptibility to Vascular Mechanical Injury

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Colon, Selene, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Bhave, Gautam B., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Group or Team Name

  • Division of Nephrology and Hypertension
Background

The normal inflammatory response consists of an immune system upregulation that protects by eliminating pathogens and promotes recovery through tissue repair. There is increasing evidence that inflamed tissues' remodeled extracellular matrix (ECM) directly affects the inflammatory response, leading to changes associated with diseases that affect various organ systems, including the vasculature and kidney.
Peroxidasin (Pxdn) is an extracellular matrix (ECM) associated heme peroxidase that catalyzes the formation of sulfilimine cross-links in collagen IV. Collagen IV is the prominent constituent of basement membranes (BM), a specialized sheet-like ECM that underlies cell layers in all tissues. The Pxdn knock-out (Pxdn-/-) mice generated in our lab exhibit reduced BM cross-links and strength. Using the unilateral nephrectomy with angiotensin II infusion (Unx + Ang II) model of kidney injury, we wanted to determine if the initiation and progression of glomerular injury depends significantly on GBM strength and resilience.

Methods

Utilizing 129S4/SvJaeJ wildtype and Pxdn-/- mice, we removed one kidney and simultaneously inserted an osmotic mini-pump for the constant subcutaneous dosing of angiotensin II, leading to hypertension-induced mechanical stress. We monitored blood pressure and body weight and collected blood and urine to measure kidney function every other week. We planned to sacrifice animals four weeks post-uninephrectomy, but Pxdn-/- female mice began to die around three weeks post-surgery. To account for this, we shortened the timeline to two weeks post-uninephrectomy.

Results

Injured female Pxdn-/- mice presented with a significant decrease in survival after 2-weeks and an increase in CD4+ T-cells and F4/80+ macrophages in the vasculature. They also had an increase in renal fibrosis and trended towards a decrease in renal function compared to all other mice. We also discovered that the exacerbated injury in female Pxdn-/- mice was reversed after ovariectomy.

Conclusion

In this work, we found that the loss of Pxdn disproportionately affects females more than males in the Unx + Ang II model of kidney injury. This dramatic vascular inflammatory phenotype is the first sex-specific phenotype attributed to Pxdn protein expression. It suggests that the loss of Pxdn and sex contribute to renal fibrosis and vascular inflammation in response to vascular mechanical injury.

Funding

  • NIDDK Support