Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling

Abstract

Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion.

Angiotensin II Dose-Dependently Stimulates Human Renal Proximal Tubule Transport by the Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate Pathway

“…Thin slices of kidney cortex were obtained from WT and cGKII KO mice, both of C57BL/6 background, 26 or Wistar rats as described. 45 Human kidney cortex tissues were obtained during the unilateral nephrectomy for renal carcinoma. The institutional review board of the University of Tokyo School of Medicine approved the study, and written informed consent was obtained from all subjects as described.…”

“…To avoid the influence of luminal transporters, the luminally collapsed tubule was used as described. 11,17,45 The tubule was incubated with the acetoxymethylester form of a pH-sensitive fluorescence dye 29,79-bis (carboxyethyl)-5(6)-carboxyfluorescein (Dojindo), and cell pH was monitored with a photometry system (OSP-10; Olympus). Prewarmed (38°C) DMEM, equilibrated with 5% CO 2 /95% O 2 gas and supplemented with 1 mM norepinephrine, which was shown to be essential for the longterm functional preservation of isolated proximal tubules, 15,46 was used for the peritubular perfusate and perfused at 10 ml/min.…”

“…The rate of cell pH decrease to bath HCO 3 2 reduction and the buffer capacity were used to calculate the NBCe1 activity as described. 11,17,45 Bath HCO 3 2 reduction (from 25 to 12.5 mM) was repeated two or three times during the control period, and only the PTs that show the constant cell pH responses were used for analysis. Valsartan, PD98059, L-NAME, ODQ, KT5823, and isobutylmethylxanthine were used at the concentrations that did not affect the basal NBCe1 activity.…”

“…The institutional review board of the University of Tokyo School of Medicine approved the study, and written informed consent was obtained from all subjects as described. 45 For the analysis of NBCe1 activity, the PT (S2 segment) fragment was microdissected manually and transferred to a perfusion chamber mounted on an inverted microscopy. Both ends of the tubule were sucked into two holding pipettes.…”

A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes

“…13) Edema has been shown to have the greatest influence compared with the other side effects, and results in the cessation of PIO; enhanced fluid retention due to the hyperactivity of Na + -HCO 3 − co-transporters expressed in the kidneys has been suggested as a mechanism responsible for edema, and the hyperactivity is not due to the PPARγ activation of PIO but the structural characteristics of PIO. 14,15) Therefore, the development of novel therapeutic agents with different structures to that of PIO are desired in order to avoid the side effects induced by TZD-type PPARγ activators.…”