Role of Rho GDP Dissociation Inhibitor α in Control of Epithelial Sodium Channel (ENaC)-mediated Sodium Reabsorption

Pavlov, Tengis S.; Levchenko, Vladislav; Staruschenko, Alexander

doi:10.1074/jbc.m114.558262

Cited by 13 publications

(5 citation statements)

References 68 publications

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“…We also investigated the involvement of Rac1 in 4% saltinduced excessive ENaC activity and found that a high-salt diet decreased the abundance of RhoGDI␣ in CDs of SS rats. Ex vivo studies revealed that low RhoGDI␣ levels augmented the bioavailability of Rac1 and activated ENaC-mediated Na ϩ reabsorption (37,62). These findings indicate that a high-salt diet leads to renal MR activation and RhoGDI␣ downregulation, which increase ENaC-mediated sodium reabsorption via higher Rac1 activity.…”

Section: F136mentioning

confidence: 86%

Involvement of ENaC in the development of salt-sensitive hypertension

Pavlov

Staruschenko

2017

American Journal of Physiology-Renal Physiology

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Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral resistance. It is commonly accepted that increased renal sodium handling and plasma volume expansion are necessary factors for the development of salt-induced hypertension. The epithelial sodium channel (ENaC) is a trimeric ion channel expressed in the distal nephron that plays a critical role in the regulation of sodium reabsorption in both normal and pathological conditions. In this mini-review, we summarize recent studies investigating the role of ENaC in the development of salt-sensitive hypertension. On the basis of experimental data obtained from the Dahl salt-sensitive rats, we and others have demonstrated that abnormal ENaC activation in response to a dietary NaCl load contributes to the development of high blood pressure in this model. The role of different humoral factors, such as the components of the renin-angiotensin-aldosterone system, members of the epidermal growth factors family, arginine vasopressin, and oxidative stress mediating the effects of dietary salt on ENaC are discussed in this review to highlight future research directions and to determine potential molecular targets for drug development.

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Section: F136mentioning

confidence: 86%

Involvement of ENaC in the development of salt-sensitive hypertension

Pavlov

Staruschenko

2017

American Journal of Physiology-Renal Physiology

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“…For example, we observed that expanded human airway stem cell-derived epithelia gradually lose CFTR-mediated chloride and ENaC-mediated sodium conductance, but interestingly they do maintain transepithelial resistance and differentiation potential. In fact, several studies (Pavlov et al, 2014; Staruschenko et al, 2004) have demonstrated the negative effect of ROCK inhibitor Y27632 and EGF on ENaC activity, which may explain the gradual decrease in ENaC-mediated sodium conductance in cells expanded in the presence of Y27632 and EGF. Partial loss of cellular physiological function in in vitro culture systems may be more common than previously recognized and may be tissue-specific and function-specific.…”

Section: Discussionmentioning

confidence: 99%

Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells

et al. 2016

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SUMMARY Functional modeling of many adult epithelia is limited by the difficulty of maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We found that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD inhibition in a feeder-free culture system we were able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium that is physiologically responsive to clinically relevant drugs such as CFTR modulators. This approach is effective for clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers, and may therefore be broadly applicable for modeling of epithelia.

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“…14 Salt-induced activation of Rac1-MR pathway in distal tubules develops salt-sensitive hypertension, 12 through augmented tubular sodium reabsorption induced by increased epithelial sodium channel (ENaC) activity. 15 Notably, the absence of severe renal injury in diabetic mice, most of which are normotensive, poses an obstacle to experimental studies related to DKD. 16 Chronic progression of DKD, which is often associated with hypertension, brings a gradual decrease in the renal function.…”

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confidence: 99%

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confidence: 99%

Activation of Rac1-Mineralocorticoid Receptor Pathway Contributes to Renal Injury in Salt-Loaded db/db Mice

et al. 2021

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The progression of diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, involves mineralocorticoid receptor (MR) activation. We previously identified crosstalk between the small guanosine triphosphatase (GTPase) RAS-related C3 botulinus toxin substrate 1 (Rac1) and MR, but the role of Rac1-MR pathway activation in the progression of DKD is not clear. We performed uninephrectomy on type 2 diabetic mouse models, db/db (UNx-high salt [HS] db/db ), and their lean control, db/m (UNx-HS db/m ), at 4-week postpartum, and fed them a high-salt diet for 10 weeks. To evaluate the involvement of the Rac1-MR pathway in the DKD progression, we investigated the effects of the nonsteroidal MR antagonist, finerenone, and the Rac1 inhibitor, NSC23766, on blood pressure and glomerular injury in UNx-HS db/db mice. UNx-HS db/db mice with hyperaldosteronism showed hypertension and hypokalemia with increased cleaved α-epithelial sodium channel expressions and massive albuminuria, accompanied by glomerular injury with nodular lesions, which is a characteristic finding in human diabetic nephropathy. Expressions of active Rac1 and serum-and glucocorticoid-induced protein kinase 1 (Sgk1), a downstream molecule of MR signaling, in the renal cortex and isolated glomeruli, significantly elevated in UNx-HS db/db mice, associated with intense staining of active Rac1 in glomerular podocytes, but both hypertension and renal injury were ameliorated by NSC23766 and finerenone, associated with Sgk1 inhibition, suggesting that Rac1-MR activation contributes to hypertension and podocyte injury. In conclusion, salt-induced activation of Rac1-MR pathway in distal tubules and glomeruli is involved in DKD progression through hypertension and glomerular injury, respectively. This finding highlights MR antagonism along with Rac1 inhibition as a novel strategy for DKD treatment.

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Role of Rho GDP Dissociation Inhibitor α in Control of Epithelial Sodium Channel (ENaC)-mediated Sodium Reabsorption

Cited by 13 publications

References 68 publications

Involvement of ENaC in the development of salt-sensitive hypertension

Involvement of ENaC in the development of salt-sensitive hypertension

Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells

Activation of Rac1-Mineralocorticoid Receptor Pathway Contributes to Renal Injury in Salt-Loaded db/db Mice

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