New perspectives on the renal slit diaphragm protein podocin

Podocin is a critical component of the glomerular filtration barrier, its mutations causing recessive steroid-resistant nephrotic syndrome. A GenBank analysis of the human podocin (NPHS2) gene resulted in the possible existence of a new splice variant of podocin in the kidney, missing the in-frame of exon 5, encoding the prohibitin homology domain. Using RT–polymerase chain reaction and immunoblotting followed by sequence analysis, we are for the first time able to prove the expression of a novel podocin isoform (isoform 2), exclusively and constitutively expressed in human podocytes. Furthermore, we reveal singular extrarenal podocin expression in human and murine testis. Our data show the Sertoli cells of the seminiferous tubules to be the origin of testicular podocin. Confocal laser microscopy illustrates the co-localization of podocin with filamentous actin within Sertoli cells, suggesting a role of podocin in the blood/testis barrier. These results led to the rationale to examine podocin expression in testes of men with Sertoli cell-only syndrome, a disorder characterized by azoospermia. Interestingly, we observed a complete down-regulation of podocin mRNA in Sertoli cell-only syndrome, indicating a possible role of podocin in the pathogenesis of this germinal aplasia. Men with Sertoli cell-only syndrome show normal renal podocin expression, suggesting an alternate regulation of the testicular promoter. Our findings may change the perception of podocin and give new insights into the ultrastructure of glomerular slit diaphragm and the blood/testis barrier

Stimulation of the calcium-sensing receptor stabilizes the podocyte cytoskeleton, improves cell survival, and reduces toxin-induced glomerulosclerosis

Calcimimetics increase the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium for efficient control of hyperparathyroidism. Recent studies suggest that there are beneficial effects of calcimimetics beyond the control of bone and mineral homeostasis. Here, we tested whether the calcium-sensing receptor is also expressed and functionally relevant in podocytes. Analysis of microarray data using Gene Set Enrichment Analysis found that the calcimimetic R-568 influenced various pathways related to oxidative stress, cytoskeletal regulation, cell proliferation, and survival in cultured podocytes. R-568 induced a dose- and time-dependent phosphorylation of the ERK1/2–P90RSK–CREB signaling cascade, and induced pro-survival phosphorylation of BAD and Bcl-xl, thus reducing puromycin aminonucleoside (PAN)-induced podocyte apoptosis by half. Moreover, R-568 preserved the actin cytoskeleton in podocytes exposed to PAN and improved recovery from exposure to cytochalasin D, a reversible inhibitor of actin polymerization. In rats, co-administration of R-568 prevented the proteinuria caused by a single dose of PAN and attenuated the glomerulosclerosis and loss of GFR caused by repetitive puromycin treatment. Hence, calcimimetics limit podocyte damage by antiapoptotic and cytoskeleton-stabilizing effects and may constitute a new approach in the prevention and treatment of glomerular disease

FGF23 induces left ventricular hypertrophy

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF–receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD