American journal of physiology. Renal physiology
-
Am. J. Physiol. Renal Physiol. · May 2010
Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells.
Peroxisome proliferator-activated receptor-γ (PPARγ) agonists ameliorate renal fibrotic lesions in diabetic nephropathy. However, the effects of the agonists on the epithelial-mesenchymal transition (EMT) linked to membrane transport dysfunction are unknown. The present study aimed to verify the effects of the PPARγ agonist troglitazone on high glucose (HG)-induced EMT in primary cultured renal proximal tubular epithelial cells (PTCs). ⋯ Finally, inhibitors of PI3K/Akt, Snail1/β-catenin siRNA, and troglitazone blocking the HG-induced EMT restored glucose uptake in PTCs. In conclusion, HG induces EMT through ROS, PI3K/Akt, GSK-3β, Snail, and β-catenin. Subsequently, HG-induced EMT may result in SGLT dysfunction that is restored by the PPARγ agonist troglitazone in primary cultured PTCs.
-
Am. J. Physiol. Renal Physiol. · Apr 2010
Hyperfiltration and inner stripe hypertrophy may explain findings by Gamble and coworkers.
Simulations conducted in a mathematical model were used to exemplify the hypothesis that elevated solute concentrations and tubular flows at the boundary of the renal outer and inner medullas of rats may contribute to increased urine osmolalities and urine flow rates. Such elevated quantities at that boundary may arise from hyperfiltration and from inner stripe hypertrophy, which are correlated with increased concentrating activity (Bankir L, Kriz W. Kidney Int. 47: 7-24, 1995). ⋯ The simulations predict that changes in boundary conditions at the boundary of the outer and inner medulla, accompanied by plausible modifications in transport properties of the collecting duct system, can significantly increase urine osmolality and flow rate. This hyperfiltration-hypertrophy hypothesis may explain the finding by Gamble et al. that the maximum urine osmolality attained from supplemental feeding of urea and NaCl in the eight intervals depends on NaCl being the initial predominant solute and on urea being the final predominant solute, because urea in sufficient quantity appears to stimulate concentrating activity. More generally, the hypothesis suggests that high osmolalities and urine flow rates may depend, in large part, on adaptive modifications of cortical hemodynamics and on outer medullary structure and not entirely on an extraordinary concentrating capability that is intrinsic to the inner medulla.
-
Am. J. Physiol. Renal Physiol. · Apr 2010
Functional implications of the three-dimensional architecture of the rat renal inner medulla.
A new, region-based mathematical model of the urine concentrating mechanism of the rat renal inner medulla (IM) was used to investigate the significance of transport and structural properties revealed in recent studies that employed immunohistochemical methods combined with three-dimensional computerized reconstruction. The model simulates preferential interactions among tubules and vessels by representing two concentric regions. The inner region, which represents a collecting duct (CD) cluster, contains CDs, some ascending thin limbs (ATLs), and some ascending vasa recta; the outer region, which represents the intercluster region, contains descending thin limbs, descending vasa recta, remaining ATLs, and additional ascending vasa recta. ⋯ In the lower IM, the model predicts that limited or nearly zero water permeability in descending thin limb segments will increase concentrating effectiveness by increasing the rate of solute-free water absorption. The model predicts that high urea permeabilities in the upper portions of ATLs and increased contact areas of longest loop bends with CDs both modestly increase concentrating capability. A surprising finding is that the concentrating capability of this region-based model falls short of the capability of a model IM that has radially homogeneous interstitial fluid at each level but is otherwise analogous to the region-based model.
-
Am. J. Physiol. Renal Physiol. · Apr 2010
Blockade of endogenous tissue kallikrein aggravates renal injury by enhancing oxidative stress and inhibiting matrix degradation.
Levels of tissue kallikrein (TK) are significantly lower in the urine of patients with kidney failure, and TK expression is specifically diminished in rat kidney after recovery from ischemia-reperfusion injury. In this study, we investigated the functional consequence of blocking endogenous TK activity in a rat model of chronic kidney disease. Inhibition of endogenous TK levels for 10 days by neutralizing TK antibody injection in DOCA-salt rats caused a significant increase in blood urea nitrogen and urinary protein levels, and a decrease in creatinine clearance. ⋯ In cultured proximal tubular cells, TK inhibited angiotensin II-induced superoxide production and NADH oxidase activity via NO formation. In addition, TK markedly increased matrix metalloproteinase-2 activity with a parallel reduction of TIMP-2 and PAI-1 synthesis. These findings indicate that endogenous TK has the propensity to preserve kidney structure and function in rats with chronic renal disease by inhibiting oxidative stress and activating matrix degradation pathways.
-
Am. J. Physiol. Renal Physiol. · Apr 2010
Role of cAMP/PKA signaling cascade in vasopressin-induced trafficking of TRPC3 channels in principal cells of the collecting duct.
Transient receptor potential channels TRPC3 and TRPC6 are expressed in principal cells of the collecting duct (CD) along with the water channel aquaporin-2 (AQP2) both in vivo and in the cultured mouse CD cell line IMCD-3. The channels are primarily localized to intracellular vesicles, but upon stimulation with the antidiuretic hormone arginine vasopressin (AVP), TRPC3 and AQP2 translocate to the apical membrane. In the present study, the effect of various activators and inhibitors of the adenylyl cyclase (AC)/cAMP/PKA signaling cascade on channel trafficking was examined using immunohistochemical techniques and by biotinylation of surface membrane proteins. ⋯ Quantification of TRPC3 membrane insertion in IMCD-3 cells under each assay condition using a surface membrane biotinylation assay, confirmed the translocation results observed by immunofluorescence. Importantly, AVP-induced translocation of TRPC3 as estimated by biotinylation was blocked on average 95.2 +/- 1.0% by H89, Rp-cAMPS, or m-PKI. Taken together, these results demonstrate that AVP stimulation of V2 receptors in principal cells of the CD causes translocation of TRPC3 to the apical membrane via stimulation of the AC/cAMP/PKA signaling cascade.