Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Abstract

Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active insideout signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.

Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

“…Podocyte loss due to cell death plays a critical role in the development of FSGS 23,24 ; a common histological manifestation of APOL1-associated kidney disease. Upon examining the mechanism of APOL1-induced cytotoxicity, we failed to observe any increase in apoptosis in APOL1 risk allele-transfected cells (Fig.…”

Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases

“…This paradigm has been deemed valid for more than 40 years (12). A major conceptual shift from immune-cell mediated to podocyte-mediated diseases occurred by realizing that many inheritable forms of focal segmental glomerulosclerosis (FSGS) are caused by mutations in proteins that are important for podocyte function (reviewed in (13)). Those discoveries provided direct evidence of the essential role of podocytes in the glomerulus, and suggested that direct targeting of the pathogenic pathways within podocytes might have a beneficial effect on glomerular diseases.…”

The Kidney in Fabry Disease

“…The addition of converting enzyme inhibitors or angiotensin receptor blockers reduces podocyturia and proteinuria, as they are capable of decreasing podocyte contraction and also reducing the size pores of the glomerular basement membrane and the width of the slit diaphragms. 30 In this respect, despite proteinuria is a useful marker of kidney disease and of glomerular injury, it is not specific of the stage of kidney damage, as it can be found at any stage of chronic kidney disease. Albeit a specific treatment for the disease exists, proteinuria frequently persists, particularly as renal disease worsens.…”