Kidney Week

Abstract: SA-PO318

Aldosterone Causes Albuminuria by Inducing MMP-Mediated Glomerular Endothelial Glycocalyx Dysfunction

Session Information

• Cellular Crosstalk in Glomerular Diseases - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Butler, Matthew J., University of Bristol, Bristol, United Kingdom

Matthew J. Butler,

• Ramnath, Raina D., University of Bristol, Bristol, United Kingdom

Raina D. Ramnath,

• Kadoya, Hiroyuki, University of Southern California, Los Angeles, California, United States

Hiroyuki Kadoya,

• Foster, Rebecca R., University of Bristol, Bristol, United Kingdom

Rebecca R. Foster,

• Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States

Janos Peti-Peterdi,

• Satchell, Simon C., University of Bristol, Bristol, United Kingdom

Simon C. Satchell,

Background

Aldosterone contributes to renal disease. Mineralocorticoid receptor (MR) inhibitors slow disease progression but side effects limit their use. Damage to the endothelial glycocalyx (glx), a luminal biopolymer layer, has been implicated in pathogenesis of endothelial dysfunction and albuminuria. We investigated if glx damage contributes to aldosterone-induced renal disease.

Methods

In vitro human glomerular endothelial cells (GEnC) were exposed to 0.1nM aldosterone for 5 days +/- 1μm spironolactone. In vivo mice received aldosterone (0.6μg/g/day via osmotic minipump) and 1.0% NaCl drinking water +/- 5mg/kg MMP2/9 inhibitor I.P. daily. Tail cuff blood pressure (BP) measurements were conducted after 5 days training. MMP2 activity was studied using a specific activity assay. Multiphoton microscopy was used to measure the glomerular sieving coefficient for albumin (GSC_alb) and a novel peak-to-peak method was developed to assess changes in GEnC glx thickness over time. ELISAs were used to measure syndecan-4 ectodomain concentrations and urine albumin levels.

Results

In vitro aldosterone reduced GEnC syndecan-4 ectodomain expression 0.76 fold (p=0.02) and increased MMP2 mRNA 4.5 fold (p=0.0003). Spironolactone blocked these effects. In vivo aldosterone resulted in significant albuminuria by day 10. Aldosterone increased glomerular MMP2 mRNA expression 5.3 fold (p=0.003) and plasma active MMP2 (22 vs 27ng/ml, p=0.045) without altering the systolic BP. The GSC_alb increased 7.6 fold by day 10 (p=0.0079) and the GEnC glx thickness fell from 1.1μm to 0.59μm (p=0.0013). No significant changes were detected in controls. Daily IP MMP2/9 inhibitor prevented glx loss, maintained the GSC_alb and prevented albuminuria without affecting the BP. Changes in glx depth predicted changes GSC_alb within the same glomeruli (R²=0.8185, p=0.0028), highlighting the importance of the glx in limiting albumin filtration.

Conclusion

Syndecan-4 (a key glx component and known substrate for MMP2) is shed in response to aldosterone via an MR-MMP dependent pathway. In vivo aldosterone results in significant thinning of the GEnC glx and albuminuria. MMP inhibition preserved the glx and prevented albuminuria and could represent a novel potential therapeutic strategy.

Funding

• Government Support - Non-U.S.