Changes in the activity and expression of protein phosphatase‐1 accompany the differential regulation of <scp>NHE</scp>3 before and after the onset of hypertension in spontaneously hypertensive rats

Crajoinas, Renato Oliveira; Pessoa, Thaíssa Dantas; Rodrigues, Mariliza V.; Malnic, Gerhard; Girardi, Adriana C. C.

doi:10.1111/apha.12288

Cited by 10 publications

(15 citation statements)

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“…Lower levels of phosphorylated NHE3 at the PKA consensus site serine 552 in the proximal tubule has been associated with higher NHE3 transport activity (Crajoinas et al, 2010 , 2014 ; Girardi and Di Sole, 2012 ; Pontes et al, 2015 ; Farah et al, 2016 ). As show in Figures 7A,B , the levels of NHE3 phosphorylation at serine 552 (PS552-NHE3) were much lower in HF than in sham-operated rats (39 ± 4 vs. 100 ± 3%, P < 0.01) (Figures 7A,B ).…”

Section: Resultsmentioning

confidence: 99%

“…Harvested hearts from rats were homogenized in a Polymix PX-SR 50 E homogenizer (Kinematica, AG, Switzerland) in ice-cold phosphate buffered saline (PBS) (10 mmol/L phosphate, 140 mmol/L NaCl, pH 7.4), including phosphatase inhibitors (15 mM NaF and 50 mM sodium pyrophosphate) and Halt Protease Inhibitor Cocktail (Thermo Fisher Scientific, Rockford, IL). Renal cortical homogenates were prepared as previously described (Crajoinas et al, 2014 ).…”

Section: Methodsmentioning

confidence: 99%

“…Equal amounts (25 μg) of renal cortical homogenates were resolved by SDS-PAGE and analyzed by immunoblotting using an antibody specific for phosphorylated PKA substrates (Gronborg et al, 2002 ; Crajoinas et al, 2014 ).…”

Section: Methodsmentioning

confidence: 99%

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Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

et al. 2016

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Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 ± 5 vs. 45 ± 3%, p < 0.05), and the isovolumic relaxation time decreased (33 ± 2 vs. 27 ± 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti-proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

et al. 2016

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“…PKA activity was indirectly measured via immunoblotting. Equal amounts (25 g) of plasma membrane protein isolated from rat renal cortices were resolved by SDS-PAGE and analyzed via immunoblotting using a specific antibody that recognizes phosphorylated PKA substrates (16). Visualized bands were digitized with an Image Scanner (GE HealthCare) and quantified with the Scion Image Software package (Scion, Frederick, MD).…”

Section: Methodsmentioning

confidence: 99%

Renal nerve stimulation leads to the activation of the Na⁺/H⁺exchanger isoform 3 via angiotensin II type I receptor

Pontes

Crajoinas

Nishi

et al. 2015

American Journal of Physiology-Renal Physiology

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Renal nerve stimulation at a low frequency (below 2 Hz) causes water and sodium reabsorption via α1-adrenoreceptor tubular activation, a process independent of changes in systemic blood pressure, renal blood flow, or glomerular filtration rate. However, the underlying mechanism of the reabsorption of sodium is not fully understood. Since the sympathetic nervous system and intrarenal ANG II appear to act synergistically to mediate the process of sodium reabsorption, we hypothesized that low-frequency acute electrical stimulation of the renal nerve (ESRN) activates NHE3-mediated sodium reabsorption via ANG II AT1 receptor activation in Wistar rats. We found that ESRN significantly increased urinary angiotensinogen excretion and renal cortical ANG II content, but not the circulating angiotensinogen levels, and also decreased urinary flow and pH and sodium excretion via mechanisms independent of alterations in creatinine clearance. Urinary cAMP excretion was reduced, as was renal cortical PKA activity. ESRN significantly increased NHE3 activity and abundance in the apical microvillar domain of the proximal tubule, decreased the ratio of phosphorylated NHE3 at serine 552/total NHE3, but did not alter total cortical NHE3 abundance. All responses mediated by ESRN were completely abolished by a losartan-mediated AT1 receptor blockade. Taken together, our results demonstrate that higher NHE3-mediated proximal tubular sodium reabsorption induced by ESRN occurs via intrarenal renin angiotensin system activation and triggering of the AT1 receptor/inhibitory G-protein signaling pathway, which leads to inhibition of cAMP formation and reduction of PKA activity.

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“…The Na + /H + exchanger 3 in the proximal tubules of the kidney has long been implicated in the development of hypertension in spontaneously hypertension in rats (SHRs; Thomas et al, 1988 , 1990 ; Kelly et al, 1997 ; Aldred et al, 2000 ; LaPointe et al, 2002 ; Kemp et al, 2014 , 2016 , 2022 ). Whether NHE3 in the proximal tubules plays any role in hypertension in SHRs remains incompletely understood ( Yip et al, 1998 ; Magyar et al, 2000 ; Panico et al, 2009 ; Crajoinas et al, 2014 ). Early in vivo micropuncture studies suggested that the development of hypertension in young SHRs up to 8 weeks of age involves sodium retention with significantly increased proximal tubule reabsorption (Jv; Thomas et al, 1988 , 1990 ).…”

Section: Nhe3 In the Proximal Tubules Of The Kidney And The Developme...mentioning

confidence: 99%

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

Nwia

Leite

et al. 2022

Front. Physiol.

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The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid–base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.

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Changes in the activity and expression of protein phosphatase‐1 accompany the differential regulation of NHE3 before and after the onset of hypertension in spontaneously hypertensive rats

Abstract: Collectively, these results support the idea that the lower NHE3 transport activity and higher phosphorylation occurring after the development of hypertension in SHRs are due, at least in part, to reduced PP1-mediated dephosphorylation of NHE3 at serine 552.

Cited by 10 publications

References 51 publications

Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

Renal nerve stimulation leads to the activation of the Na⁺/H⁺exchanger isoform 3 via angiotensin II type I receptor

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

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Changes in the activity and expression of protein phosphatase‐1 accompany the differential regulation of NHE3 before and after the onset of hypertension in spontaneously hypertensive rats

Abstract: Collectively, these results support the idea that the lower NHE3 transport activity and higher phosphorylation occurring after the development of hypertension in SHRs are due, at least in part, to reduced PP1-mediated dephosphorylation of NHE3 at serine 552.

Cited by 10 publications

References 51 publications

Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

Renal nerve stimulation leads to the activation of the Na+/H+exchanger isoform 3 via angiotensin II type I receptor

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

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Renal nerve stimulation leads to the activation of the Na⁺/H⁺exchanger isoform 3 via angiotensin II type I receptor