The Salt Paradox of the Early Diabetic Kidney Is Independent of Renal Innervation

Birk, C.; Richter, Kerstin; Huang, Danyang; Piesch, Christine; Luippold, Gerd; Vallon, Volker

doi:10.1159/000073941

Cited by 13 publications

(6 citation statements)

References 24 publications

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“…**P Ͻ 0.001 for abolition of the downward effect of HS on fractional reabsorption (middle) by coadministration of DFMO as determined by 2-way ANCOVA applied to the pooled micropuncture data with SNGFR as covariate. A reciprocal, or paradoxical, relationship between salt intake and GFR has been repeatedly demonstrated in both humans (1,3) and rats (20,21,23) with early diabetes. In seeking to identify the mechanism for this, we used a theoretical construct for the control of GFR.…”

Section: Discussionmentioning

confidence: 97%

Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

Miracle¹,

Rieg²,

Mansoury³

et al. 2008

American Journal of Physiology-Renal Physiology

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Miracle CM, Rieg T, Mansoury H, Vallon V, Thomson SC. Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt. Am J Physiol Renal Physiol 295: F995-F1002, 2008. First published June 18, 2008 doi:10.1152/ajprenal.00491.2007.-Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption (J prox) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed J prox independent of SNGFR. Suppression of J prox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes. diabetic hyperfiltration; proximal tubular reabsorption; tubuloglomerular feedback; glomerulotubular balance GLOMERULAR HYPERFILTRATION is a cardinal feature of early diabetes mellitus (5). Several lines of evidence support a tubular hypothesis to explain how glomerular filtration rate (GFR) comes to be elevated in early diabetes (reviewed in Ref. 17). According to this hypothesis, hyperfiltration is rooted in a prior increase in proximal reabsorption with GFR rising secondarily via negative feedback through the macula densa. In the course of trying to determine how the initial increase in proximal reabsorption comes about, we previously discovered that it could be prevented by suppressing growth of the kidney (15), which is normally rapid in early diabetes (10). We also discovered that proximal reabsorption in early diabetes is overly sensitive to dietary salt, to the extent that, when placed on a high salt diet, a diabetic rat drops its proximal reabsorption sufficiently to activate tubuloglomerular feedback (TGF), thereby reducing single nephron GFR (SNGFR) (20, 21). Since a reciprocal effect of dietary salt on GFR is contrary to usual expectation, we refer to this phenomenon as the salt paradox. So far, the salt parad...

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Section: Discussionmentioning

confidence: 97%

Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

Miracle¹,

Rieg²,

Mansoury³

et al. 2008

American Journal of Physiology-Renal Physiology

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show abstract

“…According to micropuncture experiments, diabetes sensitizes proximal tubular reabsorption to dietary salt, and thus via respective changes in the luminal signal of the tubuloglomerular feedback elicits the paradoxical effect of dietary salt on GFR (66). The mechanisms involved are not understood but are independent of renal nerves (8) and ANG II receptor activation (69). Further studies are required on the effect of salt intake on GFR under conditions of high fructose intake/hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

Blunted hypertensive effect of combined fructose and high-salt diet in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1

Huang

Boini²,

Friedrich³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Serum- and glucocorticoid-inducible kinase (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase stimulates the renal epithelial Na(+) channel and may thus participate in blood pressure regulation. Hyperinsulinemia is triggered by dietary fructose, which sensitizes blood pressure for salt intake. The role of SGK1 in hypertensive effects of combined fructose and high-salt intake was thus explored in SGK1 knockout mice (sgk1(-/-)) and their wild-type littermates (sgk1(+/+)). Renal SGK1 transcript levels of sgk1(+/+) mice were significantly elevated after fructose diet. Under control diet, fluid intake, urinary flow rate, urinary Na(+), K(+), and Cl(-) excretion, and blood pressure were similar in sgk1(-/-) and sgk1(+/+) mice. Addition of 10% fructose to drinking water increased fluid intake and urinary flow rate in both genotypes, and did not significantly alter urinary Na(+), K(+), and Cl(-) output in either genotype. Additional high NaCl diet (4% NaCl) did not significantly alter fluid intake and urine volume but markedly increased urinary output of Na(+) and Cl(-), approaching values significantly (P < 0.05) larger in sgk1(-/-) than in sgk1(+/+) mice (Na(+): 2,572 +/- 462 vs. 1,428 +/- 236; Cl(-): 2,364 +/- 388 vs. 1,379 +/- 225 micromol/24 h). Blood pressure was similar in sgk1(+/+) and sgk1(-/-) mice at control diet or fructose alone but increased only in sgk1(+/+) mice (115 +/- 1 vs. 103 +/- 0.7 mmHg, P < 0.05) after combined fructose and high-salt intake. Acute intravenous insulin infusion (during glucose clamp) caused antinatriuresis in sgk1(+/+) mice, an effect significantly blunted in sgk1(-/-) mice. The observations reveal a pivotal role of SGK1 in insulin-mediated sodium retention and the salt-sensitizing hypertensive effect of high fructose intake.

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“…Ang II and renal nerves are the prominent effectors that link proximal reabsorption to total body salt. Clearance experiments, however, indicate that the enhanced salt-sensitivity of proximal tubular reabsorption is not mediated by renal nerves or Ang II acting through Ang II AT1 receptors, inasmuch as chronic renal denervation (59) or chronic treatment with losartan (664) did not prevent the rise in GFR in response to low NaCl diet in STZ-diabetic rats.…”

Section: Tubular Function In Diabetesmentioning

confidence: 99%

Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

228

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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The Salt Paradox of the Early Diabetic Kidney Is Independent of Renal Innervation

Cited by 13 publications

References 24 publications

Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

Blunted hypertensive effect of combined fructose and high-salt diet in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1

Pathophysiology of the Diabetic Kidney

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