Thiazolidinediones (TZDs) are one of the major classes of
antidiabetic drugs that are used widely. TZDs improve
insulin resistance by activating
peroxisome proliferator-activated receptor gamma (PPARĪ³) and ameliorate diabetic and other nephropathies, at least, in experimental animals. However, TZDs have side effects, such as
edema,
congestive heart failure, and
bone fracture, and may increase
bladder cancer risk.
Edema and
heart failure, which both probably originate from renal
sodium retention, are of great importance because these side effects make it difficult to continue the use of TZDs. However, the pathogenesis of
edema remains a matter of controversy. Initially, upregulation of the
epithelial sodium channel (ENaC) in the collecting ducts by TZDs was thought to be the primary cause of
edema. However, the results of other studies do not support this view. Recent data suggest the involvement of transporters in the proximal tubule, such as
sodium-bicarbonate cotransporter and
sodium-
proton exchanger. Other studies have suggested that
sodium-potassium-chloride cotransporter 2 in the thick ascending limb of Henle and
aquaporins are also possible targets for TZDs. This paper will discuss the recent advances in the pathogenesis of TZD-induced
sodium reabsorption in the renal tubules and
edema.