The Renal Connexome and Possible Roles of Connexins in Kidney Diseases

Sala, G; Badalamenti, Salvatore; Ponticelli, Claudio

doi:10.1053/j.ajkd.2015.09.030

Cited by 11 publications

(5 citation statements)

References 141 publications

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“…However, in chronic high glucose/TGF-β1, as associated with diabetes, up-regulation of connexin-mediated hemichannels may overload this local diffusible route of communication. Several studies have suggested that there is a strict relationship between hemi-channel release of ATP and activation of purinergic receptors on neighbouring cells and that this may play a role in mediating the underlying pathology of various disease states [42,[51][52][53]. Having confirmed that in both acute and chronic time points, glucose/TGF-β1 evoked changes in CX expression are paralleled by reduced GJIC, we wanted to determine if hemi-channel activity increased as a compensatory mechanism to maintain cell-to-cell communication.…”

Section: Discussionmentioning

confidence: 99%

“…Glucose-evoked changes in gap-junction conductance and hemichannel activity have been linked to the pathology of multiple micro-vascular complications of diabetes [12‒19], and there is now considerable evidence to suggest that connexins represent a potential therapeutic target in the treatment of secondary complications of the disease [20, 21]. Evidence that connexin expression is linked to renal damage [20‒22], has led to suggestions that both hemi-channels and gap junctions may represent future therapeutic targets for the treatment of diabetic nephropathy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transforming Growth Factor Beta 1 Drives a Switch in Connexin Mediated Cell-to-Cell Communication in Tubular Cells of the Diabetic Kidney

Hills

Price

Wall

et al. 2018

Cell Physiol Biochem

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Background/Aims: Changes in cell-to-cell communication have been linked to several secondary complications of diabetes, but the mechanism by which connexins affect disease progression in the kidney is poorly understood. This study examines a role for glucose-evoked changes in the beta1 isoform of transforming growth factor (TGFβ1), on connexin expression, gap-junction mediated intercellular communication (GJIC) and hemi-channel ATP release from tubular epithelial cells of the proximal renal nephron. Methods: Biopsy material from patients with and without diabetic nephropathy was stained for connexin-26 (CX26) and connexin-43 (CX43). Changes in expression were corroborated by immunoblot analysis in human primary proximal tubule epithelial cells (hPTECs) and model epithelial cells from human renal proximal tubules (HK2) cultured in either low glucose (5mmol/L) ± TGFβ1 (2-10ng/ml) or high glucose (25mmol/L) for 48h or 7days. Secretion of the cytokine was determined by ELISA. Paired whole cell patch clamp recordings were used to measure junctional conductance in control versus TGFβ1 treated (10ng/ml) HK2 cells, with carboxyfluorescein uptake and ATP-biosensing assessing hemi-channel function. A downstream role for ATP in mediating the effects of TGF-β1 on connexin mediated cell communication was assessed by incubating cells with ATPγS (1-100µM) or TGF-β1 +/- apyrase (5 Units/ml). Implications of ATP release were measured through immunoblot analysis of interleukin 6 (IL-6) and fibronectin expression. Results: Biopsy material from patients with diabetic nephropathy exhibited increased tubular expression of CX26 and CX43 (P<0.01, n=10), data corroborated in HK2 and hPTEC cells cultured in TGFβ1 (10ng/ml) for 7days (P<0.001, n=3). High glucose significantly increased TGFβ1 secretion from tubular epithelial cells (P<0.001, n=3). The cytokine (10ng/ml) reduced junctional conductance between HK2 cells from 4.5±1.3nS in control to 1.15±0.9nS following 48h TGFβ1 and to 0.42±0.2nS after 7days TGFβ1 incubation (P<0.05, n=5). Acute (48h) and chronic (7day) challenge with TGFβ1 produced a carbenoxolone (200µM)-sensitive increase in carboxyfluorescein loading, matched by an increase in ATP release from 0.29±0.06μM in control to 1.99±0.47μM after 48hr incubation with TGFβ1 (10ng/ml; P<0.05, n=3). TGF-β1 (2-10ng/ml) and ATPγs (1-100µM) increased expression of IL-6 (P<0.001 n=3) and fibronectin (P<0.01 n=3). The effect of TGF-β1 on IL-6 and fibronectin expression was partially blunted when preincubated with apyrase (n=3). Conclusion: These data suggest that chronic exposure to glucose-evoked TGFβ1 induce an increase in CX26 and CX43 expression, consistent with changes observed in tubular epithelia from patients with diabetic nephropathy. Despite increased connexin expression, direct GJIC communication decreases, whilst hemichannel expression/function and paracrine release of ATP increases, changes that trigger increased levels of expression of interleukin 6 and fibronectin. Linked to inflammation and fibrosis, local increases in puri...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor Beta 1 Drives a Switch in Connexin Mediated Cell-to-Cell Communication in Tubular Cells of the Diabetic Kidney

Hills

Price

Wall

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

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“…Cxs are involved in several important regulatory processes in the kidney, including the renin angiotensin system, tubuloglomerular feedback, and salt and water reabsorption (Hanner, Sorensen, Holstein-Rathlou, & Peti-Peterdi, 2010). Cx43 is one of the most common Cxs, which has been found in the proximal tubule, collecting duct, nephron vasculature endothelial cells, vascular smooth muscle cells, and podocytes within the kidney (Sala et al, 2016). In diabetic nephropathy conditions, Cx43-mediated cell communication was influenced by chronic exposure to glucose-evoked transforming growth factor-β 1 (TGF-β1; Hills et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The opening and closing of GJ channels can be directly regulated by the membrane potential, intracellular pH, concentration of Ca 2+ , phosphorylation status, regulatory factors, and exogenous chemicals (Herve & Derangeon, ). Connexons are structures composed of six Cxs and various Cx subtypes are found to be expressed in kidney cells (Sala, Badalamenti, & Ponticelli, ). There is growing evidence that the expression or channel activity of GJs plays a key role in renal physiopathology and varies along with physiological and pathological situations within distinct renal compartments (Abed, Kavvadas, & Chadjichristos, ).…”

Section: Introductionmentioning

confidence: 99%

Allicin attenuates calcium oxalate crystal deposition in the rat kidney by regulating gap junction function

Lai

Liang

Zhong

et al. 2018

Journal Cellular Physiology

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Renal calculus is a global common urological disease that is closely related to crystal adhesion and renal tubular epithelial cell impairment. Gap junctions (GJs) and their components (connexins and Cxs) are involved in various pathophysiology processes, but their roles in renal calculi progression are not well defined. Our previous RNA microarray analysis suggests that GJs are one of the key predicted pathways involved in the renal calcium oxalate (CaOx) crystal rat model. In the current study, we found that the Cx43 and Cx32 expression and the GJ function decreased significantly after stimulation with CaOx or sodium oxalate (NaOx) in NRK‐52E, MDCK, and HK‐2 cells, and Cx43 expression also decreased in renal tissues in renal CaOx crystal model rats. Inhibition of Cx43 in NRK‐52E cells by small interference RNA significantly increased the CD44 and androgen receptor expression, and the adhesion between CaOx crystals and cells, which were consistent with the function of GJ inhibitors. On the other hand, after GJ function and Cx43 expression were increased by allicin, diallyl disulfide, or diallyl trisulfide, the impairment of NRK‐52E cells by NaOx or other GJ inhibitors and the adhesion between CaOx crystals and renal cells decreased significantly. Furthermore, allicin also increased Cx43 expression and inhibited crystal deposition in rat kidneys. Taken together, our results provide a basis that GJs and Cx43 may participate in renal CaOx stone progression and that allicin, together with its analogues, could be potential drugs for renal calculus precaution.

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“…In fact, gap junctional intercellular communication (GJIC) is actively involved in virtually all aspects of the cellular life cycle, ranging from cell growth to cell death, such as cell proliferation, migration, and apoptosis [60]. They are also related to a wide variety of diseases and pathological processes, including congenital [61] or acquired disorders related, including some related to the heart [62][63][64], brain [65,66], kidney [67,68], among many others. It highlights the fact that gap junctions have been described associated in various ways with cancer [69][70][71][72], either as a cause or consequence [73].…”

Section: Discussionmentioning

confidence: 99%

Ouabain Enhances Gap Junctional Intercellular Communication by Inducing Paracrine Secretion of Prostaglandin E2

Toro

Jimenez

Rubi

et al. 2021

IJMS

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Ouabain is a cardiac glycoside that has been described as a hormone, with interesting effects on epithelial physiology. We have shown previously that ouabain induces gap junctional intercellular communication (GJIC) in wild, sensitive cells (MDCK-S), but not in cells that have become insensitive (MDCK-I) by modifying their Na+-K+-ATPase. We have also demonstrated that prostaglandin E2 (PGE2) is able to induce increased GJIC by a mechanism other than ouabain, that does not depend on Na+-K+-ATPase. In this work we show, by dye transfer assays, that when MDCK-S and MDCK-I are randomly mixed, to form monolayers, the latter stablish GJIC, because of stimulation by a compound released to the extracellular media, by MDCK-S cells, after treatment with ouabain, as evidenced by the fact that monolayers of only MDCK-I cells, treated with a conditioned medium (CM) that is obtained after incubation of MDCK-S monolayers with ouabain, significantly increase their GJIC. The further finding that either (1) pre-treatment with COX-2 inhibitors or (2) addition to CM of antagonists of EP2 receptor abolish CM’s ability to induce GJIC in MDCK-I monolayers indicate that PGE2 is the GJIC-inducing compound. Therefore, these results indicate that, in addition to direct stimulation, mediated by Na+-K+-ATPase, ouabain enhances GJIC indirectly through the paracrine production of PGE2.

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The Renal Connexome and Possible Roles of Connexins in Kidney Diseases

Cited by 11 publications

References 141 publications

Transforming Growth Factor Beta 1 Drives a Switch in Connexin Mediated Cell-to-Cell Communication in Tubular Cells of the Diabetic Kidney

Transforming Growth Factor Beta 1 Drives a Switch in Connexin Mediated Cell-to-Cell Communication in Tubular Cells of the Diabetic Kidney

Allicin attenuates calcium oxalate crystal deposition in the rat kidney by regulating gap junction function

Ouabain Enhances Gap Junctional Intercellular Communication by Inducing Paracrine Secretion of Prostaglandin E2

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