PP2B-dependent NO production in the medullary thick ascending limb during diabetes

Foster, Jan M.; Carmines, Pamela K.; Pollock, Jennifer S.

doi:10.1152/ajprenal.90760.2008

Cited by 22 publications

(27 citation statements)

References 52 publications

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“…Nonetheless, WT mice had significantly greater NOS1, both the 160-and 130-kDa bands [two-way ANOVA, P ϭ 0.007 (160-kDa band) and P ϭ 0.014 (130-kDa band) for genotype]. The 160-kDa band for NOS1 [possibly the NOS1-␣ isoform (20)] appeared to be virtually absent in the KO mice, even with a longer exposure (Fig. 7A).…”

Section: Resultsmentioning

confidence: 97%

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Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule

Garikepati

Tsukerman

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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To elucidate the role of the insulin receptor (IR) on kidney nitric oxide generation and blood pressure (BP) control, we generated mice with targeted deletion of renal tubule IR using loxP recombination driven by a Ksp-cadherin promoter. Male knockout (KO) and wild-type (WT) littermates (~4 mo old) were transitioned through three 1-wk treatments: 1) low-NaCl diet (0.085%); 2) high-NaCl diet (HS; 5%); and 3) HS diet plus 3 mM tempol, a superoxide dismutase mimetic, in the drinking water. Mice were then switched to medium-NaCl (0.5%) diet for 5 days and kidneys harvested under pentobarbital anesthesia. Twenty-four-hour urinary nitrates plus nitrites were significantly higher in the WT mice under HS (2,067 ± 280 vs. 1,550 ± 230 nmol/day in WT and KO, respectively, P < 0.05). Tempol attenuated genotype differences in urinary nitrates plus nitrites. A rise in BP with HS was observed only in KO mice and not affected by tempol (mean arterial pressure, dark period, HS, 106 ± 5 vs. 119 ± 4 mmHg, for WT and KO, respectively, P < 0.05). Renal outer medullary protein levels of nitric oxide synthase (NOS) isoforms by Western blot (NOS1-3 and phosphorylated-S1177-NOS3) revealed significantly lower band density for NOS1 (130-kDa isoform) in the KO mice. A second study, when mice were euthanized under HS conditions, confirmed significantly lower NOS1 (130 kDa) in the KO, with an even more substantial (>50%) reduction of the 160-kDa NOS1 isoform. These studies suggest that the loss of renal IR signaling impairs renal nitric oxide production. This may be important in BP control, especially in insulin-resistant states, such as the metabolic syndrome.

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Section: Resultsmentioning

confidence: 97%

“…NOS1 (neuronal NOS or brain NOS) exists as a splice variant (NOS1-␣, NOS1-␤) (34) and is expressed in macula densa cells, TAL, and in cortical and medullary CD (29). NOS2 (inducible NOS) is found in TAL (20,32), and NOS3 (eNOS) is expressed in TAL and CD, in addition to renal endothelial cells (3,51).…”

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confidence: 99%

Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule

Garikepati

Tsukerman

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Whereas CnAa was considered to be the major isoform of the renal cortex with predominant expression in DCT, 13 we have confirmed that in TAL, CnAb is the dominant isoform. 27 Codistribution of CnAb with cyclophilin A and its paralogue, cyclophilin B, suggests that complexes composed of the calcineurin inhibitor CsA and one or both cyclophilin isoforms may form in TAL to locally inhibit CnAb phosphatase activity. 20 Calcineurin inhibitors may of course affect a variety of systemic and renal parameters via activation of the intrarenal renin-angiotensin system and modulation of the release of nitric oxide or endothelin-1.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl− Cotransporter

Borschewski

Himmerkus

Boldt

et al. 2016

Journal of the American Society of Nephrology

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The furosemide-sensitive Na + -K + -2Cl 2 -cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin Ab isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with Atype repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin Ab in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin Ab. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Ab and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Ab and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors. The furosemide-sensitive renal Na + -K + -2Cl 2 -cotransporter (NKCC2) mediates the transepithelial NaCl reabsorption in the thick ascending limb (TAL) and plays an essential role in the urinary concentration and volume regulation. 1 The transport activity of NKCC2 depends on its phosphorylation at several N-terminal, conserved threonine and serine residues, including T96, T101, and T114. 2,3 These threonines have been identified as targets for the two closely related STE20-like kinases, SPAK (SPS-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), 4,5 whereas much less information is known on the identity of the respective phosphatases. Calcineurin, a ubiquitously expressed calcium-/calmodulin-

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“…Glomeruli were homogenized as described above with total protein determined by the Bradford method (BioRad Laboratories). Samples (20 g) were assessed by standard SDSpolyacrylamide gel electrophoresis followed by blotting to polyvinylidene difluoride membranes as described previously (Foster et al, 2009). All blots were incubated overnight with the following primary antibodies: integrin ␣ 3 antibody (goat polyclonal IgG) or integrin ␤ 1 antibody (rabbit polyclonal IgG).…”

Section: Downloaded Frommentioning

confidence: 99%

Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Saleh

Pollock²,

Pollock³

2011

J Pharmacol Exp Ther

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Selective endothelin A (ET A ) and combined ET A and ET B receptor antagonists are being investigated for use in treating diabetic nephropathy. However, the receptor-specific mechanisms responsible for producing the potential benefits have not been discerned. Thus, we determined the actions of ET A and ET B receptors on measures of glomerular function and renal inflammation in the early stages of diabetic renal injury in rats through the use of selective and combined antagonists. Six weeks after streptozotocin (STZ)-induced hyperglycemia, rats were given 2R-(4-pyrrolidine-3-carboxylic acid hydrochloride (A-182086) (10 mg/kg/day), a combined ET A/B antagonist; or vehicle for 1 week. Sham controls received STZ vehicle (saline). Hyperglycemia led to significant proteinuria, increased glomerular permeability to albumin (P alb ), nephrinuria, and an increase in total matrix metalloprotease (MMP) and transforming growth factor-␤1 (TGF-␤1) activities in glomeruli. Plasma and glomerular soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were elevated after 7 weeks of hyperglycemia. Daily administration of both ABT-627 and A-182086 for 1 week significantly attenuated proteinuria, the increase in P alb , nephrinuria, and total MMP and TGF-␤1 activity. However, glomerular sICAM-1 and MCP-1 expression was attenuated with ABT-627, but not A-182086, treatment. In summary, both selective ET A and combined ET A/B antagonists reduced proteinuria and glomerular permeability and restored glomerular filtration barrier component integrity, but only ET A -selective blockade had antiinflammatory and antifibrotic effects. We conclude that selective ET A antagonists are more likely to be preferred for the treatment of diabetic kidney disease.

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PP2B-dependent NO production in the medullary thick ascending limb during diabetes

Cited by 22 publications

References 52 publications

Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule

Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule

Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl− Cotransporter

Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

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