Protecting Podocytes: A Key Target for Therapy of Focal Segmental Glomerulosclerosis

Abstract

Background: Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury demonstrated by renal biopsy that can arise from a diverse range of causes and mechanisms. It has an estimated incidence of 7 per 1 million and is the most common primary glomerular disorder leading to end-stage renal disease in the United States. This review focuses on damage to the podocyte and the consequences of this injury in patients with FSGS, the genetics of FSGS, and approaches to treatment with a focus on the effects on podocytes. Summary: The podocyte is central to the glomerular filtration barrier and is particularly vulnerable because of its highly differentiated post-mitotic phenotype. The progressive structural changes involved in the pathology of FSGS include podocyte foot process effacement, death of podocytes and exposure of the glomerular basement membrane, filtration of nonspecific plasma proteins, expansion of capillaries, misdirected filtration at points of synechiae, and mesangial matrix proliferation. Although damage to and death of podocytes can result from single-gene disorders, evidence also suggests a role for soluble factors, such as soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine-1, and anti-CD40 antibodies, that promote FSGS recurrence post transplant. Several classes of medications, including corticosteroids, calcineurin inhibitors, endothelin receptor antagonists, adrenocorticotropic hormone, and rituximab, have been shown to be effective for the treatment of FSGS and have been demonstrated to have significant protective effects on podocytes. Key Messages: Greater understanding of podocyte biology is essential to the identification of new treatment targets and medications for the management of patients with FSGS.

Membranous Nephropathy: Approaches to Treatment

“…It is one of a series of articles summarizing presentations and discussions from a roundtable discussion focused on proteinuria in nephrotic syndrome [5].…”

Proteinuria in Nephrotic Syndrome: Mechanistic and Clinical Considerations in Optimizing Management

“…Continuing with the critical role of the podocyte in maintaining normal glomerular function, our article, "Protecting Podocytes: a Key Target for Therapy of Focal Segmental Glomerulosclerosis" [2], focuses on damage to the podocyte and the consequences of other structural changes in patients with focal segmental glomerulosclerosis (FSGS). It is increasingly recognized that FSGS is not a disease itself but, rather, a histologic pattern of injury that can arise from diverse causes and mechanisms.…”

ACTH4-10 protects the ADR-injuried podocytes by stimulating B lymphocytes to secrete IL-10

“…confirmed that podocyte injury is the main pathological change associated with CKD [3,4]. At present, adrenocorticotropic hormone (ACTH) is one of the most effective therapeutic regimens for CKD, and its underlying mechanism has been intensively studied [5,6]. In our previous research, we have confirmed that ACTH 4 − 10 (10 µg/L) can directly protect the podocytes from adriamycin (ADR)-induced injury [7].…”

“…6) Compared with the normal control group, the mRNA and protein expression of nephrin and podocin 9 significantly decreased in the ADR group (p < 0.05). And ACTH [4][5][6][7][8][9][10]…”

“…However, the elevation effect was not in a dose-dependent manner. It was found that following 10 µg/L ACTH [4][5][6][7][8][9][10] treatment, the level of IL-10 secretion was significantly elevated (p < 0.05).…”