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Abstract: FR-OR028

Damage to the Mesangium Mediates the Loss of Podocytes in Glomerular Hypertension

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Kriz, Wilhelm, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany
  • Groene, Hermann-Josef, German Cancer Research Center, Heidelberg, Germany
Background


Glomerular hypertension damages the glomerulus leading to progressive glomerular disease. It is widely believed that increased perfusion pressure exposes the tuft to increased tensile stress challenging the adhesion of podocytes to the GBM favouring their detachment. This hypothesis has been based on the view that podocyte foot processes, like pericyte processes, actively counteract the pressure-driven expansion of the GBM and fail in hypertension.
Recent findings have compromised this view. Instead, counteraction of tensile stress to the filtration barrier seems to be almost exclusively performed by the GBM. The GBM displays a non-linear elasticity (Janmey and Tyler Miller 2011, J Cell Sci 124:9) meaning that its distensibility progressively decreases with increasing distension and finally reaches a limit. Thus, the expansion of a glomerular capillary and thus the expansile challenge to podocytes have an upper limit (Kriz and Lemley 2017, Ped.Nephrol 32:405). Podocytes are protected from any unphysiological pressure rises by the GBM.

Methods


High resolutiion light microscopy and transmission electron microscopy.

Results

In hypertensive models and in biopsies from patients with nephrosclerosis local disruptions of mesangial cell GBM connections are a common finding. They are consistently associated with expansions of mesangial spaces and bulging capillaries. These changes have been described in many previous studies. However, the danger that results from such local derangements of the tuft architecture to podocytes has never been adequately recognized. Here we show that such changes are topographically correlated with centrifugal displacements of capillary loops and corresponding podocytes. Depending on the location of the mesangial damage this may lead to a prolapse of podocytes into the urinary orifice with subsequent detachment of podocytes into the urine or to contacts with the parietal epithelium. Such contacts may initiate the formation of a tuft adhesion at any site of the tuft circumference, thus the committed lesion to develop focal segmental sclerosis (FSGS).

Conclusion


A combined failure of mesangial cells and podocytes underlies the development of FSGS in hypertensive glomerular diseases. The same dependence of a podocyte damage on a preceding mesangial failure is also seen in glomerular diseases, in which mesangial-cell-GBM-connections are directly damaged.