Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors

Phisitkul, Sorot; Hacker, Callenda; Simoni, Jane M.; Tran, Ruc; Wesson, Donald E.

doi:10.1038/sj.ki.5002647

Cited by 131 publications

(154 citation statements)

References 20 publications

(34 reference statements)

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“…The magnitude of this effect is also sufficient to override a simultaneous increase in extrarenal endogenous acid production. This observation contrasts with the results in rats where bosentan elicited a decrease in extrarenal acid production, a finding which, in itself, might explain the bosentan-induced decrease in distal acidification in that species (10,23). The reason(s) for this discrepancy between species is (are) not apparent.…”

Section: Discussioncontrasting

confidence: 55%

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans

Pallini

Hulter

Muser

et al. 2012

American Journal of Physiology-Renal Physiology

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-Endothelin-1 inhibits collecting duct sodium reabsorption and stimulates proximal and distal tubule acidification in experimental animals both directly and indirectly via increased mineralocorticoid activity. Diet-induced acid loads have been shown to increase renal endothelin-1 activity, and it is hypothesized that increased dietary acid-induced endothelin-1 activity may be a causative progression factor in human renal insufficiency and that this might be reversed by provision of dietary alkali. We sought to clarify, in normal human volunteers, the role of endothelin-1 in renal acidification and to determine whether the effect is dependent on dietary sodium chloride. Acid-base equilibrium was studied in seven normal human volunteers with experimentally induced metabolic acidosis [NH 4Cl 2.1 mmol·kg body weight (BW) Ϫ1·day Ϫ1 ] with and without inhibition of endogenous endothelin-1 activity by the endothelin A/B-receptor antagonist bosentan (125 BID p.o./day) both during dietary NaCl restriction (20 mmol/day) and NaCl repletion (2 mmol NaCl·kg BW Ϫ1 ·day Ϫ1 ). During NaCl restriction, but not in the NaCl replete state, bosentan significantly increased renal net acid excretion in association with stimulation of ammoniagenesis resulting in a significantly increased plasma bicarbonate concentration (19.0 Ϯ 0.8 to 20.1 Ϯ 0.9 mmol/l) despite a decrease in mineralocorticoid activity and an increase in endogenous acid production. In pre-existing human metabolic acidosis, endothelin-1 activity worsens acidosis by decreasing the set-point for renal regulation of plasma bicarbonate concentration, but only when dietary NaCl provision is restricted. metabolic acidosis; endothelin-1; bosentan; renal acidification; mineralocorticoids OF THE THREE REPORTED ENDOTHELINS (ET-1-3), ET-1 is most important for renal function with expression in renal endothelial cells, mesangium, proximal tubule, and collecting duct (13). The biologic effects of ET-1 are mediated by ET-receptors (ET-A and ET-B). ET-A is present throughout the renal and systemic vasculature (27) and also in collecting duct and proximal tubule (6,7,13). ET-B is expressed in renal endothelial cells and throughout the nephron.While known chiefly as vasoconstrictors, ETs are also reported to modulate renal sodium reabsorption and renal proton secretion (25). ET-1, through activation of ET-B, inhibits collecting duct sodium and water reabsorption. The finding that collecting duct-specific knockout of ET-1 causes hypertension and sodium retention (1) provides strong evidence that renal ET-1 is an important physiological regulator of renal Na excretion and systemic blood pressure.ET-1, through activation of ET-B, has also been shown to stimulate proximal tubule acidification by enhancing proximaltubular Na/H exchange (NHE3, via c-src activation). Distal tubule acidification in rats is also stimulated by systemic administration of ET-1, and the effect of ETs is mediated both by increased proton secretion and decreased HCO 3 Ϫ secretion (10, 11, 31, 32). Both indirect and dir...

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Section: Discussioncontrasting

confidence: 55%

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans

Pallini

Hulter

Muser

et al. 2012

American Journal of Physiology-Renal Physiology

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“…Although some observations pointed to a beneficial effect of acidosis in experimental renal disease in rodents, 28,32,33 the bulk of observations indicate that alkali treatment has beneficial and acidosis exacerbatory effects in experimental CKD. [34][35][36][37] Moreover, clinical studies in humans demonstrate that acidosis accelerates and alkali treatment retards the progression of CKD. 34,39,[74][75][76] Along those lines, decreased bicarbonate concentrations are associated with decline of eGFR in community-living older persons.…”

Section: Discussionmentioning

confidence: 99%

“…38 Moreover, administration of alkali retards the progression of CKD in rodents. [34][35][36][37] In humans with CKD, acidosis is associated with worse kidney function, whereas the administration of bicarbonate, as shown in several studies, is associated with the slowing of progressive kidney disease. 37,39 Acidosis can be induced by dietary NH 4 Cl.…”

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confidence: 99%

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NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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Klotho, a cofactor in suppressing 1,25(OH) 2 D 3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH) 2 D 3 , Ca 2+ , and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH 4 Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice .12-fold in males and .4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH) 2 D 3 , Ca 2+ , and phosphate. NH 4 Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH 4 Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH 4 Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH 4 Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH 4 Cl treatment. In conclusion, NH 4 Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH 4 Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5-dependent osteochondrogenic signaling.

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“…In previous studies, MA was found to activate a series of regulatory mechanisms to compensate for disordered acid-base balance, including complement activation, 30 endothelin production, and activation of the renin-angiotensin system. [31][32][33] This subsequently induced additional kidney damage. However, in contrast with clinical consequences such as the development of a catabolic state, 34 development or exacerbation of bone disease, 35 and deterioration of kidney function, 36 the decisive mechanism by which MA induces cellular dysfunction was largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Autophagic Clearance of Mitochondria in the Kidney Copes with Metabolic Acidosis

Namba¹,

Takabatake²,

Kimura

et al. 2014

Journal of the American Society of Nephrology

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Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent proteintagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH 4 Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule-specific autophagydeficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3-tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy.

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Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors

Cited by 131 publications

References 20 publications

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Autophagic Clearance of Mitochondria in the Kidney Copes with Metabolic Acidosis

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