Role of ultrastructural determinants of glomerular permeability in ultrafiltration function loss
Andrea Remuzzi, Sara Conti, Bogdan Ene-Iordache, Susanna Tomasoni, Paola Rizzo, Ariela Benigni, Giuseppe Remuzzi
Andrea Remuzzi, Sara Conti, Bogdan Ene-Iordache, Susanna Tomasoni, Paola Rizzo, Ariela Benigni, Giuseppe Remuzzi
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Research Article Nephrology

Role of ultrastructural determinants of glomerular permeability in ultrafiltration function loss

Abstract

The epithelial filtration slit is a crucial component of the glomerular capillary membrane, which is essential for maintaining glomerular filtration function. Though chronic kidney diseases are an immense clinical problem, the mechanisms through which structural alterations reduce glomerular water filtration have not yet been understood completely. To investigate the mechanisms underlying filtration function loss, we studied rats with spontaneously occurring progressive kidney disease, either treated with angiotensin II antagonist or untreated, combining high-resolution electron microscopy of the glomerular capillary wall with theoretical water filtration modeling. Under pathological conditions, epithelial filtration pores and the extension of the subpodocyte space were larger than in normal controls. Numerical analyses indicated that these ultrastructural changes increased hydraulic resistance of the glomerular capillary wall by extending coverage of the filtration barrier by the subpodocyte space, with the changes in hydrodynamic forces acting on podocytes likely being responsible for their detachment. Angiotensin II inhibition normalized the subpodocyte space’s hydraulic resistance, restored mechanical podocyte load, and preserved CD151–α3 integrin complex assembly, improving podocyte adherence and survival. Our results show that ultrastructural changes in podocytes are major determinants of the hydraulic resistance of the glomerular capillary wall and highlight the mechanism of podocyte loss in kidney disease progression, as well as the mechanisms underlying angiotensin II inhibition.

Authors

Andrea Remuzzi, Sara Conti, Bogdan Ene-Iordache, Susanna Tomasoni, Paola Rizzo, Ariela Benigni, Giuseppe Remuzzi

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Figure 6

Schematic representation of the cascade of events that lead to changes in glomerular capillary wall function as a consequence of podocyte changes.

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Schematic representation of the cascade of events that lead to changes i...
(A) In untreated MWF rats, the hemodynamic stress induced by expanded SPS exposes podocytes to an increase in the hydrodynamic detaching forces that tend to detach podocytes from the GBM, disrupting CD151–α3 integrin complex assembly, with changes that reduce water filtration and facilitate albumin filtration. (B) In ACE inhibitor–treated MWF rats, CD151–α3 integrin complex assembly is preserved and SPS expansion is reduced, so the physical forces acting on podocytes through filtered water are lowered and podocyte loss is limited, preserving the permselective properties of the glomerular capillary wall to albumin filtration. (C) Schematic diagram of the pathogenesis of progressive glomerular disease toward glomerulosclerosis. Initial podocyte changes activate a vicious cycle in the glomerular capillary membrane, wherein disruption of CD151–α3 integrin complex assembly leads to podocyte detachment and the expansion of SPS, which in turn causes an increase in SPS hydraulic resistance and in the resulting detaching force, thereby perpetuating podocyte depletion and glomerulosclerosis.