Malignant Hypertension a Vicious Circle of Podocyte Injury

Renal injuries induced by increased intra-glomerular pressure coincide with podocyte damage and proteinuria. In previous study we have demonstrated that in a direct response to pressure, podocytes increase Angiotensin-II and via AT1 receptors to structural changes in adhesion proteins, culminating in viable detachment. The aim of this study was to investigate the pathophysiologic effect of malignant hypertension on podocyte mitochondrial functions, NOX4, SOD2 and inflammation

METHODS

Conditionally Immortalized Human Podocyte cells developed by Saleem(UK) subjected to an in-vitro model of malignant hypertension. Cells were exposed to high hydrostatic pressure for 1h, to mimic the incidence of malignant hypertension.

Podocytes were placed in mesangial cell media pre-exposed to pressure to simulate the paracrine effect. Mitochondrial function, NOX4, SOD2, Angiotensin-II, and inflammatory mediators detachment and integrinβ1 expression were evaluated

RESULTS

Pressure enforcement:

Augmented detachment of viable/apoptotic cells with decrease in β1-integrins on the surface of podocytes mediated via AT1/AT2

• Decreased mitochondrial membrane potential accompanied by a reduction of SOD2
• Mesangial pre-exposed to pressure release exaggerated amounts of Angiotensin-II ,TGFβ1.

Podocytes placed in this media induced an inflammation increase via TGFβ1 and Il6. Increase of NOX4 and decline of SOD2 resulted in mitochondrial membrane potential decrease mediated via AT1/AT2 leading to massive apoptosis

CONCLUSIONS

• Malignant hypertension, induced mitochondrial dysfunction combined with structural changes and detachment of podocyte due to increase Angiotensin-II.
• The paracrine effect, mediated by increase production of Angiotensin-II by the mesangial cells, increase apoptosis and enhance mitochondrial dysfunction via decrease SOD2, increase oxidative stress by activation of NOX4, and enhance inflammation.