Dysregulation of Cationic Channels in Chronic Kidney Diseases

According to the Centers for Disease Control and Prevention, one in 10 American adults, has some level of chronic kidney disease (CKD), a condition characterized by reduced kidney function over time. Although recent research has uncovered many pathways and mechanisms involved in the pathophysiology of kidney diseases, this has not yet led to development of new drugs for the treatment of patients with these conditions. In this dissertation, we introduce two potential therapeutic targets for different forms of CKD. First, we discuss gating properties of the transient receptor potential cationic-6 (TRPC6) channel, then we show dysregulation of this channel in models of focal segmental glomerulosclerosis (FSGS). In a separate chapter, we introduce another channel protein, the N-methyl-D-aspartate (NMDA) receptor, as a potential therapeutic target for treatment of diabetic nephropathy. Much of this work entailed making whole-cell recordings from highly specialized kidney cells called podocytes. This technique was used to measure TRPC6 channel activity in cells in vitro, as well as in ex vivo preparations in which podocytes are still attached to the isolated glomerular capillary. Serum samples from a variety of primary FSGS patient groups were obtained from collaborators. We used the sera to treat our cells in vitro and investigate the effect of soluble factors in the patients’ serum on the activity and expression levels of TRPC6 channels. Regarding the other target, we studied the effect of NMDA inhibitors in alleviating the development of diabetic nephropathy in vivo. I concluded that TRPC6 channels are dysregulated in FSGS. This suggested that further development of TRPC6 inhibitors might be warranted as potential therapeutic agents. We observed that diabetes caused a marked increase in the expression of renal NMDA receptors, and that sustained treatment with NMDA antagonists reduces the progression of nephropathy in two mouse models of type-1 diabetes. Consequently, it is possible that this class of drugs can be useful for reducing the progression of nephropathy.