NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip

Ren, Huiwen; Yang, Baoxue; Molina, Patrick A.; Sands, Jeff M.; Klein, Janet D.

doi:10.1371/journal.pone.0141714

Cited by 19 publications

(11 citation statements)

References 43 publications

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“…Blots were scanned and ImageJ (NIH) was used to quantitate lane protein density. We normalized each protein of interest to the loading control (31). …”

Section: Methodsmentioning

confidence: 99%

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

Efe¹,

Klein²,

LaRocque³

et al. 2016

JCI Insight

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Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/ kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl− cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI.

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“…Blots were scanned and ImageJ (NIH) was used to quantitate lane protein density. We normalized each protein of interest to the loading control (31). …”

Section: Methodsmentioning

confidence: 99%

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

Efe¹,

Klein²,

LaRocque³

et al. 2016

JCI Insight

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“…Image J (NIH) was used to quantitate lane protein density. We normalized each protein of interest to the loading control [17]. The amounts of protein loaded per well are as follows: 20μg for UT-A1, 30μg for AQP2 and 30μg for NKCC2.…”

Section: Methodsmentioning

confidence: 99%

Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

Chen

LaRocque

Efe

et al. 2016

The American Journal of the Medical Sciences

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Aim This study evaluates the effect of dapagliflozin, a SGLT2 inhibitor, on fluid/electrolyte balance and its effect on urea transporter-A1 (UT-A1), aquaporin-2 (AQP2) and Na-K-2Cl cotransporter (NKCC2) protein abundance in diabetic rats. Methods Diabetes mellitus was induced by injection of streptozotocin into the tail vein. Serum Na+, K+, Cl− concentration, urine Na+, K+, Cl− excretion, blood glucose, urine glucose excretion, urine volume, urine osmolality and urine urea excretion were analyzed after the administration of dapagliflozin. UT-A1, AQP2 and NKCC2 proteins were detected by western blot. Results Dapagliflozin treatment decreased blood glucose by 38% at day 7 and 47% at day 14 and increased the urinary glucose excretion rate compared with the untreated diabetic animals. Increased 24-h urine volume, decreased urine osmolality and hyponatremia, hypokalemia and hypochloremia observed in diabetic rats were attenuated by dapagliflozin treatment. Western analysis showed that UT-A1, AQP2 and NKCC2 proteins are up-regulated in DM rats over control rats; dapagliflozin treatment results in a further increase in IM tip UT-A1 protein abundance by 42% at day 7 and 46% at day 14, but it did not affect the DM-induced up-regulation of AQP2 and NKCC2 proteins. Conclusion Dapagliflozin treatment augmented the compensatory changes in medullary transport proteins in DM. These changes will tend to conserve solute and water even with persistent glycosuria. Therefore, diabetic rats treated with dapagliflozin have a mild osmotic diuresis compared to non-diabetic animals, but this does not result in an electrolyte disorder or significant volume depletion.

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“…It also localises in the β-laminin of the glomerular basement membrane [19]. AQP-2, a urine concentration regulator under anti-diuretic hormone, is located at the apical membrane of the collecting duct [22]. AQP-4, a water permeability regulator, is located at the basolateral membrane of the collecting duct and exports water into the cytoplasm via AQP-2 [20].…”

Section: Discussionmentioning

confidence: 99%

Streptozotocin induces alpha-2u globulin nephropathy in male rats during the end-stage of diabetic kidney disease

Kengkoom¹,

Angkhasirisap²,

Kanjanapruthipong³

et al. 2020

Preprint

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Background Alpha-2u globulin nephropathy mainly shows toxicological pathology only in male rats induced by certain chemicals and drugs, such as levamisole (antiparasitic and anticancer drugs). Streptozotocin (STZ) is also an anticancer-antibiotic agent that has been used for decades to induce a diabetic kidney disease model in rodents. The purpose of this study is to determine if STZ causes alpha-2u globulin nephropathy in male rats during an advanced stage of diabetic kidney disease. Methods To prove this hypothesis, the present study used a male diabetic Wistar rat model with 45 mg/kg of STZ injected intraperitoneally. Hyperglycaemic rats were divided into 2 groups: with and without end-stage kidney disease. Alpha-2u globulin nephropathy was examined by histopathological and electron microscope studies. Water absorption and filtration capacities (via aquaporin [AQP]-1, -2, -4 and -5) and mitochondrial function (through haloacid dehalogenase-like hydrolase domain-containing protein [HDHD]-3 and NADH-ubiquinone oxidoreductase 75 kDa subunit [NDUFS]-1 proteins) were determined using immunohistochemistry, immunofluorescence and immunogold labelling techniques. Results More than 80% of end-stage diabetic kidney disease induced by STZ injection simultaneously exhibited alpha-2u globulin nephropathy with mitochondrial degeneration and filtration apparatus especially pedicels impairment. They also showed significantly upregulated AQP-1, -2, -4 and -5, HDHD-3 and NDUFS-1 compared with those of the rats without alpha-2u globulin nephropathy. Conclusions STZ-induced alpha-2u globulin nephropathy during end-stage diabetic kidney disease in association with deterioration of renal filtration, renal tubular damage with adaptation and mitochondrial apoptosis.

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NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip

Cited by 19 publications

References 43 publications

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus

Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

Streptozotocin induces alpha-2u globulin nephropathy in male rats during the end-stage of diabetic kidney disease

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