The Evidence-Based Use of Thiazide Diuretics in Hypertension and Nephrolithiasis

Reilly, Robert F.; Peixoto, Aldo J.; Desir, Gary V.

doi:10.2215/cjn.04670510

Cited by 52 publications

(26 citation statements)

References 82 publications

(65 reference statements)

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“…Thiazides are the specific inhibitors of NCC in the distal tubule and the most widely used diuretic in the world, in large part because they are considered mild agents and do not cause severe salt wasting (16,17). The DCT is responsible for the reabsorption of 7-10% of filtered salt, and published reports indicate that majority of this process is mediated via NCC (18,19).…”

Section: Discussionmentioning

confidence: 99%

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Soleimani

Barone

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

133

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The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe salt wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.diuretics | kidney tubules | nephrogenic diabetes insipidus T he thiazide-sensitive Na-Cl cotransporter (NCC) (SLC12A3) and the Cl − /HCO 3 − exchanger pendrin (SLC26A4) are expressed on apical membranes of distal cortical nephron segments and mediate salt absorption, with pendrin working in tandem with the epithelial Na channel and NCC working by itself (1-6). Pendrin is expressed on the apical membrane of intercalated cells in late distal convoluted tubule (DCT), connecting tubule (CNT), and the cortical collecting duct (CCD) (7-9). The thiazide-sensitive NCC is primarily expressed on the apical membrane of DCT cells (10,11).Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions (5,(12)(13)(14)(15). Indeed, even a mild degree of salt wasting has not been demonstrated in these two genetically engineered mouse models at steady state. Kidney functions, including sodium and chloride excretion, urine output, and blood urea nitrogen (BUN) levels in mutant mice are comparable to wild-type (WT) animals (12-15). Both pendrin KO and NCC KO mice, however, show signs of volume depletion or develop hypotension during salt restriction (12,14). These findings have led investigators to conclude that pendrin and NCC are predominantly active during salt depletion (and or in response to increased aldosterone levels), and their contribution to salt reabsorption at baseline conditions is small.We hypothesized that NCC and pendrin may compensate for loss of the other under basal conditions, thereby masking the role that each plays in salt reabsorption. To test this hypothesis, we generated double knockout of pendrin and NCC mice by crossing animals with single deletion for NCC and pendrin. The double KO mice show significant salt and flui...

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Section: Discussionmentioning

confidence: 99%

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Soleimani

Barone

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

133

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“…Based on these results, NEDD4-2 appears to primarily target NCC and might thus be an attractive target to treat hypertension, avoiding the most severe side effect of thiazides, namely hypokalemia. Moreover, there is an interesting clinical association of hypercalciuria with hypertension and an increased risk of nephrolithiasis in hypertension (47)(48)(49)(50). Defects in NEDD4-2 could therefore underlie these associations, and its study could lead to important mechanistic insights.…”

Section: Figurementioning

confidence: 99%

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Ronzaud¹,

Loffing‐Cueni²,

Hausel³

et al. 2013

J. Clin. Invest.

100

158

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The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na + channel (ENaC/SCNN1) to mediate Na + homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and highNa + diets, conditional KO mice displayed decreased plasma aldosterone but normal Na + /K + balance. Under a high-Na + diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K + channel (ROMK), and total and phosphorylated thiazide-sensitive Na + Cl -cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na + /K + balance maintained by downregulation of ENaC activity and upregulation of ROMK.

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“…Further modification of the benzothiadiazine core led to the synthesis of hydrochlorothiazide (HCTZ) and the thiazide-like diuretics: chlorthalidone (phthalimidine), metolazone (quinazolinone), and indapamide (indoline). Indapamide binds and inhibits the Na 1 -Cl 2 cotransporter in the distal convoluted tubule and connecting tubule but does not contain the benzothiadiazine core (Reilly et al, 2010). Despite similarities to other members of the thiazide family, indapamide has unique features that render it a particularly efficacious and advantageous antihypertensive agent (Sassard et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Indapamide Lowers Blood Pressure by Increasing Production of Epoxyeicosatrienoic Acids in the Kidney

Lin

Chen

et al. 2013

Mol Pharmacol

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Diuretics are widely used in the treatment of hypertension, although the precise mechanisms remain unknown. Epoxyeicosatrienoic acids (EETs), cytochrome P450 (P450) epoxygenase metabolites of arachidonic acid, play critical roles in regulation of blood pressure. The present study was carried out to investigate whether EETs participate in the antihypertensive effect of thiazide diuretics [hydrochlorothiazide (HCTZ)] and thiazide-like diuretics (indapamide). Male spontaneously hypertensive rats (SHRs) were treated with indapamide or HCTZ for 8 weeks. Systolic blood pressure, measured via tail-cuff plethysmography and confirmed via intra-arterial measurements, was significantly decreased in indapamide-and HCTZ-treated SHRs compared with salinetreated SHRs. Indapamide increased kidney CYP2C23 expression, decreased soluble epoxide hydrolase expression, increased urinary and renovascular 11,12-and 14,15-EETs, and decreased production of 11,12-and 14,15-dihydroxyeicosatrienoic acids in SHRs. No effect on expression of CYP4A1 or CYP2J3, or on 20-hydroxyeicosatetraenoic acid production, was observed, suggesting indapamide specifically targets CYP2C23-derived EETs. Treatment of SHRs with HCTZ did not affect the levels of P450s or their metabolites. Increased cAMP activity and protein kinase A expression were observed in the renal microvessels of indapamide-treated SHRs. Indapamide ameliorated oxidative stress and inflammation in renal cortices by down-regulating the expression of p47phox, nuclear factor-kB, transforming growth factor-b1, and phosphorylated mitogen-activated protein kinase. Furthermore, the p47phox-lowering effect of indapamide in angiotensin II-treated rat mesangial cells was partially blocked by the presence of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) or CYP2C23 small interfering RNA. Together, these results indicate that the hypotensive effects of indapamide are mediated, at least in part, by the P450 epoxygenase system in SHRs, and provide novel insights into the blood pressure-lowering mechanisms of diuretics.

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The Evidence-Based Use of Thiazide Diuretics in Hypertension and Nephrolithiasis

Cited by 52 publications

References 82 publications

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Indapamide Lowers Blood Pressure by Increasing Production of Epoxyeicosatrienoic Acids in the Kidney

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