Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia

Alves, Daiane S.; Thulin, Gunilla; Loffing, Johannes; Kashgarian, Michael; Caplan, Michael J.

doi:10.1681/asn.2013101040

Cited by 18 publications

(11 citation statements)

References 54 publications

(76 reference statements)

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“…Because AS160 is important for both muscle and adipose GLUT4 trafficking, these models are unable to address tissue-specific contributions. Additionally, AS160 has alternate roles in the heart ( 48 ) and renal epithelial cells ( 49 ), which would have also been affected. Hence, our AR10KO model was designed to be tissue specific and to probe not only the relevance of Rab10, but also of glucose uptake, specifically in the insulin stimulated state.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance

et al. 2016

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Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes.

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Section: Discussionmentioning

confidence: 99%

Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance

et al. 2016

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“…It has been suggested that Na–K‐ATPase plays an additional significant role in altered tubular sodium handling after I/R, particularly in the PT (especially in the S3 segment) and the outer medullary TAL, which are known to be the segments most affected by ischemic insult (Alves et al. ). In our study, immunohistochemistry showed that Na–K‐ATPase staining seemed weaker in the OM alone in I/R kidneys compared to both sham‐ and rIPeC‐treated I/R kidneys, indicating that regulation of Na–K‐ATPase in response to I/R and rIPeC is more confined to this kidney zone compared to the rest of the kidney.…”

Section: Discussionmentioning

confidence: 99%

Remote ischemic perconditioning attenuates ischemia/reperfusion-induced downregulation of AQP2 in rat kidney

et al. 2016

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Renal ischemia/reperfusion (I/R) can lead to impaired urine concentration ability and increased fractional excretion of sodium (FeNa). Local ischemic preconditioning improves renal water and sodium handling after I/R injury. Here, we investigate whether remote ischemic perconditioning (rIPeC) prevents dysregulation of renal water and salt handling in response to I/R injury and mechanisms that may be involved. Rats were subjected to right nephrectomy and randomized into a sham group or an I/R group. In the I/R group, rats were subjected to 37 min of renal ischemia and 3 days of reperfusion. rIPeC was applied to the abdominal aorta. Blood and urine were collected on day 3 postoperatively for clearance studies. The expression of aquaporins (AQPs) and the sodium transporter Na–K‐ATPase were analyzed using immunoblotting and immunohistochemistry. I/R injury resulted in polyuria, increased FeNa, and decreased urine osmolality compared to sham rats. rIPeC attenuated the increase in FeNa and the decrease in urine osmolality. Expression of AQP1, AQP2, phosphorylated AQP2 (pAQP2), and Na–K‐ATPase was downregulated in I/R rats. rIPeC attenuated the reductions in AQP2 and pAQP2 expression. Immunohistochemistry revealed decreased labeling of Na–K‐ATPase in the outer medulla in I/R kidneys compared to kidneys from sham and I/R + rIPeC rats. After renal ischemia, the expression of Na–K‐ATPase was substantially reduced in the outer medullary thick ascending limb. In conclusion, our data suggest that rIPeC might prevent dysregulation of renal water and salt handling via regulation of AQP2 expression and phosphorylation as well as via regulation of Na–K‐ATPase expression in I/R rat kidneys.

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“…The Na + -K + -ATPase is a ubiquitous transmembrane protein that transports three Na + out of and two K + into the cell for maintaining cell membrane potential and intracellular ion homeostasis [4]. Numerous studies indicate the involvement of Na + -K + -ATPase in development of many diseases, including renal injury [5,6]. For example, decreased Na + -K + -ATPase activity has been reported in injured kidney cells, renal damage animal models and even in renal patients [5,7,8].…”

Section: Introductionmentioning

confidence: 99%

DR region specific antibody ameliorated but ouabain worsened renal injury in nephrectomized rats through regulating Na,K-ATPase mediated signaling pathways

Wang

Ullah

et al. 2019

Aging

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Reduced Na + -K + -ATPase function is reported in various renal diseases. This implies that increase of Na + -K + -ATPase function may be a new target in treatment of renal injury. We previously reported that Na + -K + -ATPase was stabilized by DRm217, a specific antibody against DR region of Na + -K + -ATPase. In this study, we compared the protective effect of DRm217 and ouabain on kidney in a chronic kidney disease rat model and investigated the mechanism under it. We found that DRm217 improved renal function, alleviated glomerulus atrophy, inhibited renal tubular cells apoptosis, tubulointerstitial injury and renal fibrosis in 5/6 nephrectomized rats. Contrary to DRm217, ouabain worsened renal damage. Activated Na + -K + -ATPase /Src signaling pathway, increased oxidant stress and activated inflammasome were responsible for nephrectomized or ouabain-induced renal injury. DRm217 inhibited Na + -K + -ATPase /Src signaling pathway, retarded oxidant stress, suppressed inflammasome activation, and improved renal function, suggesting a novel approach to prevent renal damage.

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Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia

Cited by 18 publications

References 54 publications

Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance

Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance

Remote ischemic perconditioning attenuates ischemia/reperfusion-induced downregulation of AQP2 in rat kidney

DR region specific antibody ameliorated but ouabain worsened renal injury in nephrectomized rats through regulating Na,K-ATPase mediated signaling pathways

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