Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes

Song, Jian; Knepper, Mark A.; Verbalis, Joseph G.; Ecelbarger, Carolyn A.

doi:10.1152/ajprenal.00143.2003

Cited by 58 publications

(50 citation statements)

References 31 publications

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“…Similarly, E 2 replacement normalized the expression of ␣-and ␤-ENaC, which were reduced in diabetic female rats. Decreased ␣-and ␤-ENaC in the chronically diabetic female rats contrasted with our earlier finding in male rats, which were diabetic for only 4 days (142). The reasons underlying these discrepancies are not clear.…”

Section: Altered Expression Of Sodium Transporter and Channels In Diacontrasting

confidence: 98%

“…E 2 replacement in STZ-diabetic rats altered the ratio of estrogen receptor subtypes in the kidney (164) and also attenuated the severity of the diabetes, as measured by a reduction in the hyperglycemia in these rats (124). With regard to changes in transport proteins, NKCC2 abundance was increased by diabetes in the whole kidney and outer medulla, as in our earlier short-term (4-day) study previously described (142). E 2 replacement normalized NKCC2 expression.…”

Section: Altered Expression Of Sodium Transporter and Channels In Diasupporting

confidence: 66%

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Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes

Tiwari

Riazi²,

Ecelbarger³

2007

American Journal of Physiology-Renal Physiology

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112

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Insulin has been shown to have antinatriuretic actions in humans and animal models. Moreover, endogenous hyperinsulinemia and insulin infusion have been correlated to increased blood pressure in some models. In this review, we present the current state of understanding with regard to the regulation of the major renal sodium transporters by insulin in the kidney. Several groups, using primarily cell culture, have demonstrated that insulin can directly increase activity of the epithelial sodium channel, the sodium-phosphate cotransporter, the sodium-hydrogen exchanger type III, and Na-K-ATPase. We and others have demonstrated alterations in the expression at the protein level of many of these same proteins with insulin infusion or in hyperinsulinemic models. We also discuss how this regulation is perturbed in type I and type II diabetes mellitus. Finally, we discuss a potential role for regulation of insulin receptor signaling in the kidney in contributing to sodium balance and blood pressure. insulin resistance; ENaC; Zucker rats; streptozotocin Overview INSULIN HAS BEEN DEMONSTRATED to increase sodium reabsorption in the proximal tubule (9), the thick ascending limb (78, 102), and the distal tubule including the collecting duct (54, 144), using micropuncture and perfused tubule approaches. Over 10 years ago, Sechi (127), Butlen (30), and colleagues using I 125 -labeled insulin demonstrated binding sites in multiple cell types along the renal tubular epithelium. However, because the kidney expresses other receptors similar to the classic insulin receptor (IR), including the insulin growth factor receptor (IGF) and the IR-related receptor (IRR), the precise nature of the "receptor" that labeled insulin was binding to was not absolutely certain. Nonetheless, more recent studies showed mRNA expression of the classic IR in whole homogenates of the kidney (31, 32,130,132), and our group (150) has recently found IR expression at the protein level using immunoblotting and immunohistochemistry in the proximal tubule, thick ascending limb, and collecting duct. In this review, we discuss studies that have investigated the regulation of the major renal sodium transporters in the kidney by insulin. In addition, we examine how this regulation is altered in insulin resistance, which is a hyperinsulinemic state, as well as in type I and type II diabetes. We also discuss what is known about the regulation of the IR in the kidney, how it is affected by insulin resistance and/or diabetes, and how this might ultimately affect sodium balance and blood pressure.

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Section: Altered Expression Of Sodium Transporter and Channels In Diacontrasting

confidence: 98%

Section: Altered Expression Of Sodium Transporter and Channels In Diasupporting

confidence: 66%

Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes

Tiwari

Riazi²,

Ecelbarger³

2007

American Journal of Physiology-Renal Physiology

Self Cite

112

View full text Add to dashboard Cite

show abstract

“…It is, thus, unlikely that the increase in HSP expression we observed in the diabetic outer medulla was secondary to STZ-induced tubular injury. In both human and experimental diabetes, there is a reduction in oxygen tension, particularly in the outer medulla, and overexpression of tubular carrier proteins in outer medullary thick ascending limbs, which enhance sodium chloride reabsorption and interstitial osmolarity (11,33). The increased hypertonic and hypoxic stress in the diabetic outer medulla may induce an overexpression of HSP localized specifically to this area, which, in turn, may result in cytoprotection and counterbalance diabetes-induced cell injury.…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein expression in diabetic nephropathy

Barutta¹,

Pinach²,

Giunti³

et al. 2008

American Journal of Physiology-Renal Physiology

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Heat shock protein (HSP) HSP27, HSP60, HSP70, and HSP90 are induced by cellular stresses and play a key role in cytoprotection. Both hyperglycemia and glomerular hypertension are crucial determinants in the pathogenesis of diabetic nephropathy and impose cellular stresses on renal target cells. We studied both the expression and the phosphorylation state of HSP27, HSP60, HSP70, and HSP90 in vivo in rats made diabetic with streptozotocin and in vitro in mesangial cells and podocytes exposed to either high glucose or mechanical stretch. Diabetic and control animals were studied 4, 12, and 24 wk after the onset of diabetes. Immunohistochemical analysis revealed an overexpression of HSP25, HSP60, and HSP72 in the diabetic outer medulla, whereas no differences were seen in the glomeruli. Similarly, exposure neither to high glucose nor to stretch altered HSP expression in mesangial cells and podocytes. By contrast, the phosphorylated form of HSP27 was enhanced in the glomerular podocytes of diabetic animals, and in vitro exposure of podocytes to stretch induced HSP27 phosphorylation via a P38-dependent mechanism. In conclusion, diabetes and diabetesrelated insults differentially modulate HSP27, HSP60, and HSP70 expression/phosphorylation in the glomeruli and in the medulla, and this may affect the ability of renal cells to mount an effective cytoprotective response. mesangial cells; glomerular epithelial cells; mechanical stretch DIABETIC NEPHROPATHY (DN), the leading cause of end-stage renal failure in the Western world, is characterized by increased albumin excretion rate (AER) and progressive decline in renal function (9,20). Both hyperglycemia and glomerular capillary hypertension are considered major determinants in the onset and the progression of the complication (5), and in vitro studies on renal cells exposed to high glucose and/or mechanical stretch have partially clarified the underlying cellular mechanisms for this disorder (13).Heat shock proteins (HSP) are ubiquitous, highly evolutionary conserved intracellular proteins categorized according to their molecular weight (10). Thermal, oxidative, hemodynamic, osmotic, and hypoxic stresses (17) induce HSP60, HSP27 (human)/HSP25 (rodents), and HSP70 (human)/HSP72 (rodents), and HSP90 expression, and this stress response results in cytoprotection (18). Specifically, HSP prevent nonspecific protein assembly, assist in denatured protein refolding, and interfere with proapoptotic pathways. Both hyperglycemia and glomerular capillary hypertension impose cellular stresses on renal target cells and they are thus potential inducers of a stress response that may counterbalance the deleterious effects of these insults. In addition, enhanced expression/phosphorylation of HSP27, an actin-specific molecular chaperone, has been reported in podocytes in experimental nephrotic syndrome (32), suggesting a role for HSP27 in the pathophysiological changes of the podocyte cytoskeleton during the development of proteinuria. Liu et al. (19) have demonstrated that HSP47, a procolla...

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“…Loss-of-function mutations of NCC (Gitelman syndrome) cause renal salt wasting with hypotension, hypokalemic alkalosis, and hypocalciuria, 3 whereas increased NCC activity because of mutations within the NCC-regulating with-no-lysine kinase 1 (WNK1) or WNK4 (familial hyperkalemic hypertension) are associated with severe salt-sensitive hypertension, hyperkalemia, metabolic acidosis, and hypercalciuria. 4 Increased NCC expression has been linked to renal Na + retention in liver cirrhosis, 5 diabetes mellitus, 6 b-adrenergic stimulation, 7 and immunosuppressive treatment. 8 The clinical significance of the DCT is also emphasized by clinical trials that confirmed the DCT as an important target for antihypertensive therapy.…”

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confidence: 99%

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

Picard

Trompf

Yang

et al. 2014

Journal of the American Society of Nephrology

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The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelchlike 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na + uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1 2/2 ) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1 2/2 mice. Compared with WT mice, I-1 2/2 mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity.

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Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes

Cited by 58 publications

References 31 publications

Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes

Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes

Heat shock protein expression in diabetic nephropathy

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

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