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A Mutation in the TRPC6 Cation Channel Causes Familial Focal

In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In this Review, we discuss the latest basic and clinical research on Alport syndrome, focusing on the roles of podocyte pathology and the extracellular matrix. We also highlight early diagnosis and treatment options for young patients with this disorder.

Alport syndrome—insights from basic and clinical research

Podocytes represent an essential component of the kidney’s glomerular filtration barrier. They stay attached to the glomerular basement membrane via integrin interactions that support the capillary wall to withstand the pulsating filtration pressure. Podocyte structure is maintained by a dynamic actin cytoskeleton. Terminal differentiation is coupled with permanent exit from the cell cycle and arrest in a postmitotic state. Postmitotic podocytes do not have an infinite life span; in fact, physiologic loss in the urine is documented. Proteinuria and other injuries accelerate podocyte loss or induce death. Mature podocytes are unable to replicate and maintain their actin cytoskeleton simultaneously. By the end of mitosis, cytoskeletal actin forms part of the contractile ring, rendering a round shape to podocytes. Therefore, when podocyte mitosis is attempted, it may lead to aberrant mitosis (ie, mitotic catastrophe). Mitotic catastrophe implies that mitotic podocytes eventually detach or die; this is a previously unrecognized form of podocyte loss and a compensatory mechanism for podocyte hypertrophy that relies on post–G1-phase cell cycle arrest. In contrast, local podocyte progenitors (parietal epithelial cells) exhibit a simple actin cytoskeleton structure and can easily undergo mitosis, supporting podocyte regeneration. In this review we provide an appraisal of the in situ pathology of mitotic catastrophe compared with other proposed types of podocyte death and put experimental and renal biopsy data in a unified perspective.

New Insights into the Pathology of Podocyte Loss: Mitotic Catastrophe

Within the glomerulus, the scaffolding protein nephrin bridges the actin-rich foot processes that extend from adjacent podocytes to form the slit diaphragm. Mutations affecting a number of slit diaphragm proteins, including nephrin, cause glomerular disease through rearrangement of the actin cytoskeleton and disruption of the filtration barrier. We recently established that the Nck family of Src homology 2 (SH2)/SH3 cytoskeletal adaptor proteins can mediate nephrin-dependent actin reorganization. Formation of foot processes requires expression of Nck in developing podocytes, but it is unknown whether Nck maintains podocyte structure and function throughout life. Here, we used an inducible transgenic strategy to delete Nck expression in adult mouse podocytes and found that loss of Nck expression rapidly led to proteinuria, glomerulosclerosis, and altered morphology of foot processes. We also found that podocyte injury reduced phosphorylation of nephrin in adult kidneys. These data suggest that Nck is required to maintain adult podocytes and that phosphotyrosine-based interactions with nephrin may occur in foot processes of resting, mature podocytes.

Nck Proteins Maintain the Adult Glomerular Filtration Barrier

Diet-Induced Podocyte Dysfunction in Drosophila and Mammals.

Nephrin is involved in podocyte maturation but not survival during glomerular development. Commentary

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Nephrin is involved in podocyte maturation but not survival during glomerular development. Commentary