3/4/2023 0 Comments Fluid retention11, 12 Lower BP could reduce renal perfusion pressure, thereby increasing renal reabsorption of Na + and fluid. Investigators have proposed that TZD-induced edema formation relates to increases in vascular permeability 7 – 10 and vasodilation. 3 – 5 An important clinical limitation for this class of drugs is fluid retention and edema formation, which occurs in up to 5% of patients who have diabetes and are treated with TZDs as a consequence, these agents are contraindicated in patients with New York Heart Association classes III and IV congestive heart failure. 2 PPAR-γ is also expressed in other tissues, such as the vasculature, where TZDs affect the inflammatory response and cholesterol homeostasis. 1 Thiazolidinediones (TZDs) are potent ligands and activators of PPAR-γ and are insulin sensitizers used extensively to treat type 2 diabetes. Peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors that regulate a large number of diverse genes by transcriptional activation and repression. These data argue against a primary and critical role of ENaC in thiazolidinedione-induced fluid retention. Finally, patch-clamp studies in primary mouse inner medullary collecting duct cells did not detect ENaC activity but did detect a nonselective cation channel upregulated by pioglitazone. Moreover, treatment with rosiglitazone or pioglitazone did not significantly alter the open probability or number of ENaC channels per patch in isolated, split-open cortical collecting ducts of wild-type mice. Scnn1a loxloxCre mice provided functional evidence for blunted Na + uptake in the collecting duct, but still exhibited rosiglitazone-induced fluid retention. In control mice, rosiglitazone did not alter plasma aldosterone levels or protein expression of ENaC subunits in the kidney, but did increase body weight, plasma volume, and the fluid content of abdominal fat pads, and decreased hematocrit. To test a proposed role for the epithelial sodium channel ENaC in thiazolidinedione-induced fluid retention, we used mice with conditionally inactivated αENaC in the collecting duct (Scnn1a loxloxCre mice). Thiazolidinediones are agonists of peroxisome proliferator–activated receptor γ (PPARγ) that can induce fluid retention and weight gain through unclear mechanisms.
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