TRPC channel modulation in podocytes-inching toward novel treatments for glomerular disease.

Glomerular kidney disease is a major healthcare burden and considered to represent a sum of disorders that evade a refined and effective treatment. Excellent biological and genetic studies have defined pathways that go awry in podocytes, which are the regulatory cells of the glomerular filter. The question now is how to define targets for novel improved therapies. In this review, we summarize critical points around targeting the TRPC6 channel in podocytes.

Enzymatic disease of the podocyte.

Proteinuria is an early sign of kidney disease and has gained increasing attention over the past decade because of its close association with cardio-vascular and renal morbidity and mortality. Podocytes have emerged as the cell type that is critical in maintaining proper functioning of the kidney filter. A few genes have been identified that explain genetic glomerular failure and recent insights shed light on the pathogenesis of acquired proteinuric diseases. This review highlights the unique role of the cysteine protease cathepsin L as a regulatory rather than a digestive protease and its action on podocyte structure and function. We provide arguments why many glomerular diseases can be regarded as podocyte enzymatic disorders.

Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte ß(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte ß(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-ß(3) integrin interaction through antibodies and small molecules targeting either uPAR or ß(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.