Lithium-induced NDI in rats is associated with loss of α-ENaC regulation by aldosterone in CCD

Lithium-induced nephrogenic diabetes insipidus (Li-NDI) is associated with increased urinary sodium excretion and decreased responsiveness to aldosterone and vasopressin. Dysregulation of the epithelial sodium channel (ENaC) is thought to play an important role in renal sodium wasting. The effect of 7-day aldosterone and spironolactone treatment on regulation of ENaC in rat kidney cortex was investigated in rats with 3 wk of Li-NDI. Aldosterone treatment of rats with Li-NDI decreased fractional excretion of sodium (0.83 ± 0.02), whereas spironolactone did not change fractional excretion of sodium (1.10 ± 0.11) compared with rats treated with lithium alone (1.11 ± 0.05). Plasma lithium concentration was decreased by aldosterone (0.31 ± 0.03 mmol/l) but unchanged with spironolactone (0.84 ± 0.18 mmol/l) compared with rats treated with lithium alone (0.54 ± 0.04 mmol/l). Immunoblotting showed increased protein expression of α-ENaC, the 70-kDa form of γ-ENaC, and the Na-Cl cotransporter (NCC) in kidney cortex in aldosterone-treated rats, whereas spironolactone decreased α-ENaC and NCC compared with control rats treated with lithium alone. Immunohistochemistry confirmed increased expression of α-ENaC in the late distal convoluted tubule and connecting tubule and also revealed increased apical targeting of all three ENaC subunits (α, β, and γ) in aldosterone-treated rats compared with rats treated with lithium alone. Aldosterone did not, however, affect α-ENaC expression in the cortical collecting duct (CCD), which showed weak and dispersed labeling similar to that in rats treated with lithium alone. Spironolactone did not affect ENaC targeting compared with rats treated with lithium alone. This study shows a segment specific lack of aldosterone-mediated α-ENaC regulation in the CCD affecting both α-ENaC protein expression and trafficking, which may explain the increased sodium wasting associated with chronic lithium treatment.

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Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00306.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. F540-F551 ◽

Cited By ~ 16

Author(s):

Emily Borsting ◽

Vicki Pei-Chun Cheng ◽

Chris K. Glass ◽

Volker Vallon ◽

Robyn Cunard

Keyword(s):

Protein Expression ◽

Sodium Channel ◽

Mrna Expression ◽

Collecting Duct ◽

Epithelial Sodium Channel ◽

Duct Cell ◽

Kidney Cortex ◽

Peroxisome Proliferator ◽

Cortical Collecting Duct ◽

Peroxisome Proliferator Activated Receptor

Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, ∼5% of patients experience the treatment-limiting side effect of edema. Studies have implicated activation of the epithelial sodium channel (ENaC) as a cause of TZD-induced fluid retention, although there have been conflicting reports. The goal of this study was to resolve the role of PPARγ in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPARγ ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaCα and ENaCβ mRNA and ENaCγ protein expression in the kidney cortex, and acute treatment for 5 h with pioglitazone, another potent TZD, does not increase renal ENaC isoform mRNA or protein expression. Pioglitazone also decreases ENaCα and ENaCγ mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPARγ-dependent regulation of ENaC. Pioglitazone represses ENaCγ promoter activity, and this repression is partially relieved by inhibition of protein synthesis. Chromatin immunoprecipitation assays revealed that repression is associated with a decrease in histone H4K5 acetylation at the proximal ENaCγ promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaCγ promoter via an indirect transcriptional mechanism.

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Low endogenous glucocorticoid allows induction of kidney cortical cyclooxygenase-2 during postnatal rat development

AJP Renal Physiology ◽

10.1152/ajprenal.00099.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. F26-F37 ◽

Cited By ~ 18

Author(s):

Kirsten Madsen ◽

Jane Stubbe ◽

Tianxin Yang ◽

Ole Skøtt ◽

Sebastian Bachmann ◽

...

Keyword(s):

Kidney Development ◽

Collecting Duct ◽

Rat Kidney ◽

Plasma Concentrations ◽

Cyclooxygenase 2 ◽

Kidney Cortex ◽

Thick Ascending Limb ◽

Corticosterone Concentration ◽

Rat Kidney Cortex ◽

Cox 2

In postnatal weeks 2–4, cyclooxygenase-2 (COX-2) is induced in the rat kidney cortex where it is critically involved in final stages of kidney development. We examined whether changes in circulating gluco- or mineralocorticosteroids or in their renal receptors regulate postnatal COX-2 induction. Plasma corticosterone concentration peaked at birth, decreased to low levels at days 3- 13, and increased to adult levels from day 22. Aldosterone peaked at birth and then stabilized at adult levels. Gluco- and mineralocorticoid receptor (GR and MR) mRNAs were expressed stably in kidney before, during, and after COX-2 induction. 11β-Hydroxysteroid dehydrogenase 2 was induced shortly after birth and was widely distributed in the whole collecting duct system in the suckling period and then returned to an adult pattern. Supplementation with corticosterone (20 mg·kg-1·day-1) or GR-specific dexamethasone (1 mg·kg-1·day-1) during low endogenous corticosterone suppressed renal COX-2 mRNA and protein and led to a restricted distribution of COX-2 immunolabeling. The ability of glucocorticoids to affect COX-2 was reflected in colocalization of GR-α and COX-2 immunoreactivity and mRNAs in thick ascending limb of Henle's loop. The MR antagonist potassium canrenoate (20 mg·kg-1·day-1) enhanced COX-2 expression from days 5 to 10, but low MR-specific concentrations of DOCA (1 mg·kg-1·day-1) had no effect on COX-2. Renomedullary interstitial cells expressed GR-α and COX-2. Dexamethasone suppressed COX-2 in these cells. Thus low plasma concentrations of corticosterone allowed for cortical and medullary COX-2 induction during postnatal kidney development. Increased circulating glucocorticoid in the postnatal period may damage late renal development through inhibition of COX-2.

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Pendrin: an apical Cl−/OH−/HCO3 −exchanger in the kidney cortex

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.2.f356 ◽

2001 ◽

Vol 280 (2) ◽

pp. F356-F364 ◽

Cited By ~ 193

Author(s):

Manoocher Soleimani ◽

Tracey Greeley ◽

Snezana Petrovic ◽

Zhaohui Wang ◽

Hassane Amlal ◽

...

Keyword(s):

Proximal Tubule ◽

Collecting Duct ◽

Rat Kidney ◽

Immunoblot Analysis ◽

Kidney Cortex ◽

Cortical Collecting Duct ◽

Hek 293 ◽

Kidney Proximal Tubule ◽

293 Cells ◽

Nephron Segment

The identities of the apical Cl−/base exchangers in kidney proximal tubule and cortical collecting duct (CCD) cells remain unknown. Pendrin (PDS), which is expressed at high levels in the thyroid and its mutation causes Pendred's syndrome, is shown to be an anion exchanger. We investigated the renal distribution of PDS and its function. Our results demonstrate that pendrin mRNA expression in the rat kidney is abundant and limited to the cortex. Proximal tubule suspensions isolated from kidney cortex were highly enriched in pendrin mRNA. Immunoblot analysis studies localized pendrin to cortical brush-border membranes. Nephron segment RT-PCR localized pendrin mRNA to proximal tubule and CCD. Expression studies in HEK-293 cells demonstrated that pendrin functions in the Cl−/OH−, Cl−/HCO3 −, and Cl−/formate exchange modes. The conclusion is that pendrin is an apical Cl−/base exchanger in the kidney proximal tubule and CCD and mediates Cl−/OH−, Cl−/HCO3 −, and Cl−/formate exchange.

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Ganglioside GM2-Activator Protein and Vesicular Transport in Collecting Duct Intercalated Cells

Journal of the American Society of Nephrology ◽

10.1681/asn.v103435 ◽

1999 ◽

Vol 10 (3) ◽

pp. 435-443

Author(s):

THOMAS M. MUNDEL ◽

HANS W. HEID ◽

DON J. MAHURAN ◽

WILHELM KRIZ ◽

PETER MUNDEL

Keyword(s):

Collecting Duct ◽

Rat Kidney ◽

The Body ◽

Kidney Cortex ◽

Intercalated Cells ◽

Rat Kidney Cortex ◽

Activator Protein ◽

Hexosaminidase A ◽

Gm2 Activator ◽

Gm2 Activator Protein

Abstract. This study describes the molecular characterization of an antigen defined by an autoantibody from a woman with habitual abortion as GM2-activator protein. The patient showed no disorder of renal function. Accidentally with routine serum screening for autoantibodies, an immunoreactivity was found in kidney collecting duct intercalated cells. Three distinct patterns of immunostaining of intercalated cells were observed: staining of the apical pole, basolateral pole, and diffuse cytoplasmic labeling. Ultrastructurally, the immunoreactivity was associated with “studs,” which represent the cytoplasmic domain of the vacuolar proton pump in intercalated cells. This pump is subjected to a shuttling mechanism from cytoplasmic stores to the cell membrane, which exclusively occurs in intercalated cells. Peptide sequences of a 23-kD protein purified from rat kidney cortex showed complete identity with corresponding sequences of GM2-activator protein. In the brain, GM2-activator protein is required for hexosaminidase A to split a sugar from ganglioside GM2. Because neither ganglioside GM2 nor GM1 (its precursor) is present in significant amounts in the kidney, the previous finding that this tissue contains the highest level of activator protein in the body was confusing. In this study, a novel role for GM2-activator protein in intercalated cells is proposed, and possible roles in the shuttling mechanism are discussed.

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Low doses of ochratoxin A upregulate the protein expression of organic anion transporters Oat1, Oat2, Oat3 and Oat5 in rat kidney cortex

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2009.06.008 ◽

2009 ◽

Vol 239 (3) ◽

pp. 284-296 ◽

Cited By ~ 34

Author(s):

Vilim Žlender ◽

Davorka Breljak ◽

Marija Ljubojević ◽

Dubravka Flajs ◽

Daniela Balen ◽

...

Keyword(s):

Protein Expression ◽

Ochratoxin A ◽

Rat Kidney ◽

Organic Anion ◽

Kidney Cortex ◽

Low Doses ◽

Organic Anion Transporters ◽

Rat Kidney Cortex ◽

Anion Transporters

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Segment-specific ENaC downregulation in kidney of rats with lithium-induced NDI

AJP Renal Physiology ◽

10.1152/ajprenal.00118.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. F1198-F1209 ◽

Cited By ~ 51

Author(s):

Jakob Nielsen ◽

Tae-Hwan Kwon ◽

Jeppe Praetorius ◽

Young-Hee Kim ◽

Jørgen Frøkiær ◽

...

Keyword(s):

Sodium Excretion ◽

Sodium Intake ◽

Collecting Duct ◽

Lithium Treatment ◽

Fractional Excretion ◽

Sodium Balance ◽

Connecting Tubule ◽

Renal Sodium Excretion ◽

Fractional Excretion Of Sodium ◽

Medullary Collecting Duct

Lithium-induced nephrogenic diabetes insipidus is associated with increased renal sodium excretion in addition to severe urinary concentrating defects. However, the molecular basis for this altered renal sodium excretion remains undefined. The amiloride-sensitive sodium channel (ENaC) is expressed in the renal connecting tubule and collecting duct and is essential in renal regulation of body sodium balance and blood pressure. We hypothesized that dysregulation of ENaC subunits may be responsible for the increased sodium excretion associated with lithium treatment. Lithium treatment for 28 days resulted in severe polyuria, increased fractional excretion of sodium, and increased plasma aldosterone concentration. Immunoblotting revealed that lithium treatment induced a marked decrease in the protein abundance of β-ENaC and γ-ENaC in the cortex and outer medulla. Moreover, immunohistochemistry and laser confocal microscopy demonstrated an almost complete absence of β-ENaC and γ-ENaC labeling in cortical and outer medullary collecting duct, which was not affected by dietary sodium intake. In contrast, immunohistochemistry showed increased apical labeling of all ENaC subunits in the connecting tubule and inner medullary collecting duct in rats on a fixed sodium intake but not in rats with free access to sodium. Except for a modest downregulation of the thiazide-sensitive Na-Cl cotransporter, the key renal sodium transporters upstream from the connecting tubule (including the α1-subunit of Na-K-ATPase, type 3 Na/H exchanger, and Na-K-2Cl cotransporter) were unchanged. These results identify a marked and highly segment-specific downregulation of β-ENaC and γ-ENaC in the cortical and outer medullary collecting duct, chief sites for collecting duct sodium reabsorption, in rats with a lithium-induced increase in fractional excretion of sodium.

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Increase of Na/Pi-cotransport encoding mRNA in response to low Pi diet in rat kidney cortex.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)37420-3 ◽

1994 ◽

Vol 269 (9) ◽

pp. 6637-6639

Author(s):

A. Werner ◽

S.A. Kempson ◽

J. Biber ◽

H. Murer

Keyword(s):

Rat Kidney ◽

Kidney Cortex ◽

Rat Kidney Cortex

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Cytochrome P-450K of rat kidney cortex microsomes: Further studies on its interaction with fatty acids

Archives of Biochemistry and Biophysics ◽

10.1016/0003-9861(73)90552-3 ◽

1973 ◽

Vol 158 (2) ◽

pp. 597-604 ◽

Cited By ~ 54

Author(s):

Åke Ellin ◽

Sten Orrenius ◽

Åke Pilotti ◽

Carl-Gunnar Swahn

Keyword(s):

Fatty Acids ◽

Rat Kidney ◽

Kidney Cortex ◽

Rat Kidney Cortex

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Studies on the orientation of brush-border membrane vesicles

Biochemical Journal ◽

10.1042/bj1720057 ◽

1978 ◽

Vol 172 (1) ◽

pp. 57-62 ◽

Cited By ~ 192

Author(s):

W Haase ◽

A Schäfer ◽

H Murer ◽

R Kinne

Keyword(s):

Brush Border ◽

Brush Border Membrane ◽

Rat Kidney ◽

Freeze Fracture ◽

Membrane Vesicles ◽

Brush Border Membrane Vesicles ◽

Immunological Methods ◽

Kidney Cortex ◽

Asymmetric Distribution ◽

Rat Kidney Cortex

Orientation of rat renal and intestinal brush-border membrane vesicles was studied with two independent methods: electron-microscopic freeze-fracture technique and immunological methods. With the freeze-fracture technique a distinct asymmetric distribution of particles on the two membrane fracture faces was demonstrated; this was used as a criterion for orientation of the isolated membrane vesicles. For the immunological approach the accessibility or inaccessibility of aminopeptidase M localized on the outer surface of the cell membrane to antibodies was used. With both methods we showed that the brush-border membrane vesicles isolated from rat kidney cortex and from rat small intestine for transport studies are predominantly orientated right-side out.

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