The Role of Nitric Oxide in the Dysregulation of the Urine Concentration Mechanism in Diabetes Mellitus

Cipriani, Penelope; Kim, Sunhye L.; Klein, Janet D.; Sim, Jae Hoon; Bergen, Tobias N. von; Blount, Mitsi A.

doi:10.3389/fphys.2012.00176

Cited by 13 publications

(9 citation statements)

References 47 publications

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“…In this study, there was no comparison to diabetic rats treated with insulin, so it is not known whether the decrease of blood glucose upon dapagliflozin treatment might contribute to UT-A1 up-regulation in diabetic rat IM. However, our previous study showed that absence of nitric oxide (NO) production in kidney reduced UT-A1 protein abundance in DM[29]. Hyperglycemia is believed to play a key role in reducing NO production in kidney[30].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In opposition to us, a recent work showed an up regulation of glycosylated AQP2 in STZ-diabetic rats and found that the treatment of the animals with L-NAME suppressed the compensatory increase in AQP2 expression [48]. However, that study was performed three weeks after the induction of diabetes and the authors attributed the effect of L-NAME to the inhibition of vasopressin release.…”

Section: Discussionmentioning

confidence: 83%

Renal Response to L-Arginine in Diabetic Rats. A Possible Link between Nitric Oxide System and Aquaporin-2

et al. 2014

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The aim of this study was to evaluate whether L-Arginine (L-Arg) supplementation modifies nitric oxide (NO) system and consequently aquaporin-2 (AQP2) expression in the renal outer medulla of streptozotocin-diabetic rats at an early time point after induction of diabetes. Male Wistar rats were divided in four groups: Control, Diabetic, Diabetic treated with L-Arginine and Control treated with L-Arginine. Nitric oxide synthase (NOS) activity was estimated by [14C] L-citrulline production in homogenates of the renal outer medulla and by NADPH-diaphorase staining in renal outer medullary tubules. Western blot was used to detect the expression of AQP2 and NOS types I and III; real time PCR was used to quantify AQP2 mRNA. The expression of both NOS isoforms, NOS I and NOS III, was decreased in the renal outer medulla of diabetic rats and L-Arg failed to prevent these decreases. However, L-Arg improved NO production, NADPH-diaphorase activity in collecting ducts and other tubular structures, and NOS activity in renal homogenates from diabetic rats. AQP2 protein and mRNA were decreased in the renal outer medulla of diabetic rats and L-Arg administration prevented these decreases. These results suggest that the decreased NOS activity in collecting ducts of the renal outer medulla may cause, at least in part, the decreased expression of AQP2 in this model of diabetes and constitute additional evidence supporting a role for NO in contributing to renal water reabsorption through the modulation of AQP2 expression in this pathological condition. However, we cannot discard that another pathway different from NOS also exists that links L-Arg to AQP2 expression.

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“…This enhanced production leads to hyperfiltration and microalbuminuria characterizing early diabetic nephropathy [22,23]. Progression towards end-stage kidney disease is accompanied by a decrease in NO bioavailability, mainly due to excessive accumulation of advanced glycation end products [24,25].…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived NO in Subjects Affected by Type 2 Diabetes with and without Complications: Is there any Relationship with their Offspring?

Vignini

Salvolini

Nanetti

et al. 2017

Exp Clin Endocrinol Diabetes

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Macro- and microvascular complications are currently the principal causes of morbidity and mortality in patients with diabetes mellitus. Aim of this study was to determine if type 2 diabetic patients with nephropathy and coronary artery disease showed altered platelet-derived nitric oxide (NO) production, compared with diabetic subjects without complications, and if this alteration is also present in their diabetic offspring. In this case-control observational study, platelet NO and peroxynitrite content was determined on plasma from 60 male adult type 2 diabetic patients and 60 male offspring type 2 diabetic patients. Plasmatic levels of homocysteine were also determined in the same individuals. Moreover, Western blot analysis of platelet lysates was performed with specific monoclonal antibody for endothelial (eNOS) and inducible (iNOS) nitric oxide synthase. Our study showed a lower piastrinic production of NO in the group of parents without complications (ADH), compared with the group of offspring without complications (YDH) and with the groups of parents with complications. Furthermore, we observed a lower synthesis of peroxynitrite in platelets from the ADH group than in the groups of patients with complications, and in the YDH group compared with all other groups. Subjects from YDH group also showed lower iNOS expression, compared with all other groups. Our data suggest that alterations in nitric oxide metabolism may represent potential risk factors in type 2 diabetes complications, such as nephropathy and cardiovascular diseases, leading to development of new therapeutic strategies in order to delay and prevent the onset of such complications.

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The Role of Nitric Oxide in the Dysregulation of the Urine Concentration Mechanism in Diabetes Mellitus

Cited by 13 publications

References 47 publications

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

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

Renal Response to L-Arginine in Diabetic Rats. A Possible Link between Nitric Oxide System and Aquaporin-2

Platelet-Derived NO in Subjects Affected by Type 2 Diabetes with and without Complications: Is there any Relationship with their Offspring?

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