Dipeptidyl peptidase IV inhibition downregulates Na<sup>+</sup>-H<sup>+</sup>exchanger NHE3 in rat renal proximal tubule

Girardi, Adriana C. C.; Fukuda, Lívia Emy; Rossoni, Luciana Venturini; Malnic, Gerhard; Rebouças, Nancy Amaral

doi:10.1152/ajprenal.00174.2007

Cited by 89 publications

(78 citation statements)

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“…The proximal tubule reabsorbs approximately two-thirds of the NaCl that enters the tubular fluid by glomerular filtration 30 mediated by transport proteins. [31][32][33] The proximal tubule Na þ transporters on which OA exerts inhibitory action could not be identified by the current observations, nor is it clear whether OA has a direct effect on epithelial transport or works through an intermediary. Na þ is mainly reabsorbed across the proximal tubular cell in a process mediated by proximal tubule apical NHE3 followed by uphill active extrusion via basolateral Na þ /K þ ATPase.…”

Section: Discussionmentioning

confidence: 70%

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

et al. 2012

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Studies indicate that Syzygium spp-derived oleanolic acid (OA) enhances renal function of streptozotocin (STZ)-induced diabetic rats as evidenced by its reversal of the previously reported inability of the kidney to excrete Na þ in these animals. We postulated that OA influences Na þ excretion in the proximal tubule, the site where two-thirds of filtered NaCl is reabsorbed through a process mediated by transport proteins. Therefore, the study investigated the effects of OA on proximal tubular Na þ handling in male Sprague-Dawley rats using renal lithium clearance (C Li ). Renal C Li has been used widely in animal and clinical studies to assess proximal tubular function. Sub-chronic doses of OA were administered to rats twice every third day for 5 weeks. Rats treated with deionized water served as control animals. Cytotoxicity of OA on kidney and liver cell lines was assessed by the MTT and comet assays. OA increased Na þ excretion of conscious male Sprague-Dawley rats from week 3 to week 5. By the end of the 5-week experimental period, OA treatment significantly reduced (p < 0.05) plasma creatinine concentration of STZ-induced diabetic rats with a concomitant elevation in glomerular filtration rate (GFR). Acute OA infusion was also associated with increases in fractional excretion of sodium (FE Na ) and lithium (FE Li ) in anesthetized rats in the absence of significant changes in GFR. The MTT assay studies demonstrated that OA increased the metabolic activity of kidney and liver cell lines. Taken together with previous observations, this study implicates the proximal tubule in OA-evoked increases in urinary Na þ output.

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Section: Discussionmentioning

confidence: 70%

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

et al. 2012

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“…Studies in an opossum kidney proximal tubule cell line showed that inhibitors of DPP-4 (diprotin A and P32/98) significantly reduced NHE3 activity (17). Treatment of rats with the DPP-4 inhibitor Lys [Z(NO 2 )]-pyrrolidide for 7 days decreased NHE activity in isolated proximal tubular microvillar membrane vesicles, redistributed NHE3 from the apical enriched microvillar membranes to the intermicrovillar microdomain of the brush border, and increased fractional Na ϩ excretion and Li ϩ clearance (16). Moreover, intratubular application of GLP-1 or EX4, but not the DPP-4 inhibitor P32/98, reduced the rate of bicarbonate flux during stationary in vivo microperfusion in proximal convoluted tubules, i.e., during the absence of flow and glomerular filtrate reaching the site of study (6).…”

Section: Discussionmentioning

confidence: 98%

“…The DPP-4 inhibitors Lys [Z(NO 2 )]-pyrrolidide and P32/98 inhibited NHE3-mediated Na ϩ reabsorption in rat renal proximal tubule in vivo (6,16). Studies in an opossum kidney proximal tubule cell line indicate that the enzymatic activity of DPP-4 in the proximal tubular brush border may locally affect the generation or breakdown of endogenous factors that regulate Na ϩ reabsorption via effects on NHE3 activity (17).…”

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confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

131

111

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Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na ϩ reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na ϩ excretion, and renal membrane expression of the Na ϩ /H ϩ exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na ϩ reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.glucagon-like peptide-1; dipeptidyl peptidase-4; NHE3; cAMP; proximal tubule GLUCAGON-LIKE PEPTIDE -1 (GLP-1), an incretin hormone secreted from enteroendocrine L cells in the intestine, stimulates glucose-dependent insulin release and may promote preservation of beta-cell function in patients with type 2 diabetes (9, 10). As a consequence, GLP-1 has been a principal focus of clinical and basic diabetes research in recent years. After secretion, active GLP-1 is rapidly cleaved by the widely expressed enzyme dipeptidyl peptidase-4 (DPP-4, CD26), such that the half-life of bioactive GLP-1 is Ͻ3 min. Therefore, therapeutic manipulation of the GLP-1 system includes strategies that inhibit the degradation of GLP-1 by DPP-4 (i.e., DPP-4 inhibitors) or degradation-resistant GLP-1 receptor (GLP-1R) agonists with a longer half-life, such as exendin-4 (EX4) or liraglutide.In addition to its metabolic effects, GLP-1 affects kidney function. Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6, 30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in...

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“…Furthermore, a lack of validation of the anti‐megalin antibody is a limitation of this study; however, megalin single band demarcations were localized in the expected molecular weight size (Figure S1) plus other studies had successfully used the same antibody previously (Girardi et al. 2008; Gressner et al. 2008; Tsaroucha et al.…”

Section: Discussionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC‐5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24‐h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC‐5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real‐time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC‐5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low‐molecular‐weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

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Dipeptidyl peptidase IV inhibition downregulates Na⁺-H⁺exchanger NHE3 in rat renal proximal tubule

Abstract: Girardi AC, Fukuda LE, Rossoni LV, Malnic G, Rebouças NA. Dipeptidyl peptidase IV inhibition downregulates Na ϩ -H ϩ exchanger NHE3 in rat renal proximal tubule.

Cited by 89 publications

References 50 publications

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

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Dipeptidyl peptidase IV inhibition downregulates Na+-H+exchanger NHE3 in rat renal proximal tubule

Abstract: Girardi AC, Fukuda LE, Rossoni LV, Malnic G, Rebouças NA. Dipeptidyl peptidase IV inhibition downregulates Na ϩ -H ϩ exchanger NHE3 in rat renal proximal tubule.

Cited by 89 publications

References 50 publications

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

The Effects ofSyzygium aromaticum-Derived Oleanolic Acid on Kidney Function of Male Sprague–Dawley Rats and on Kidney and Liver Cell Lines

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

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Dipeptidyl peptidase IV inhibition downregulates Na⁺-H⁺exchanger NHE3 in rat renal proximal tubule