The podocyte as a direct target for treatment of glomerular disease?

Abstract

The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans, have chronic kidney disease (CKD). A failure to maintain the glomerular filtration barrier directly contributes to the onset of CKD. The visceral epithelial cells, podocytes, are integral to the maintenance of this renal filtration barrier. Direct podocyte injury contributes to the onset and progression of glomerular diseases such as minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, and HIV-associated nephropathy (HIVAN). Since podocytes are terminally differentiated with minimal capacity to self-replicate, they are extremely sensitive to cellular injury. In the past two decades, our understanding of the mechanism(s) by which podocyte injury occurs has greatly expanded. With this newfound knowledge, therapeutic strategies have shifted to identifying targets directed specifically at the podocyte. Although the systemic effects of these agents are important, their direct effect on the podocyte proves to be essential in ameliorating glomerular disease. In this review, we highlight the mechanisms by which these agents directly target the podocyte independent of its systemic effects.

Focal Segmental Glomerulosclerosis

“…Current therapy for primary FSGS is on the basis of immunosuppressive agents; it is now apparent that a number of these, including glucocorticoids and calcineurin inhibitors, directly modulate the podocyte phenotype (57). Recently, it has been shown that the effects of glucocorticoids may be mediated by Krüppel factor 15, a zinc finger transcription factor (57,58).…”

“…Recently, it has been shown that the effects of glucocorticoids may be mediated by Krüppel factor 15, a zinc finger transcription factor (57,58). In a recent retrospective case series involving 476 subjects, the use of glucocorticoids and/or cyclosporin was associated with improved outcomes compared to no immunosuppression, with a hazard ratio of 0.49 (95% CI, 0.28 to 0.86) for ESRD whereas the use of cyclosporine with or without glucocorticoids was not associated with benefit HR 0.42 (95% CI, 0.15 to 1.18) (59).…”

Quercetin liposomes ameliorate streptozotocin-induced diabetic nephropathy in diabetic rats

“…This difference in the peak time can be explained by the slow release of PEGL carrier. Increased kidney weight caused by diabetes indicates renal hypertrophy, a common finding in the early stages of diabetes 25,26 . In this study, interstitial fibrosis, mesangial contraction, and structural remodeling contributed to the decrease in renal hypertrophy, and improved renal function reduced the 24-h urinary protein.…”

Targeting strategies for drug delivery to the kidney: From renal glomeruli to tubules

“…53 Podocytes constitute 21% to 34% of the total glomerular cell population, and podocytopathy can lead to minimal change disease, membranous nephropathy, focal and segmental glomerulosclerosis, membranous nephropathy, collapsing glomerulopathy, and diabetic nephropathy. 54,55 These are often the initiating cause of renal diseases that result in proteinuria and even ESRD. For these reasons, drug therapy directed to the MCs and podocytes is hypothesized to more effectively treat glomerular diseases than conventional nondirectional drug therapy.…”