An emerging role for calcineurin Aα in the development and function of the kidney

Gooch, Jennifer

doi:10.1152/ajprenal.00281.2005

Cited by 37 publications

(39 citation statements)

References 49 publications

(47 reference statements)

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“…Another research found that there is only a small amount of CaN expression in a normal kidney, mainly in renal proximal tubules. 18 Gooch et al 19,20 reported that CaN expression in kidney tissue increased, and the activity of CaN phosphatase also upregulated in the early stage of diabetes. CaN played an important role in glomerulosclerosis of DN, and inhibiting CaN could obviously alleviate the degree of glomerulosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Chen

Liu

et al. 2011

Renal Failure

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Objective: To investigate the effects of norcantharidin (NCTD) on tubulointerstitial fibrosis of diabetic nephropathy (DN) in streptozotocin-induced rat model. Methods: Sprague-Dawley rats were randomly divided into control group, model group, low-dose NCTD (0.05 mg/kg/day) group, and high-dose NCTD (0.1 mg/kg/day) group. The model group was induced by injection intraperitoneally with 30 mg/kg streptozotocin in 0.1 mol/L sodium citrate solution (pH 4.5), after high-calorie foods were given for 2 months. NCTD was administered daily after the DN rat model was built. Rats were sacrificed at the end of the third and the eighth week; renal fibrosis and the expression of FN, collagen IV, TGF-b1, and calcineurin (CaN) were detected by Masson and immunohistochemistry staining, respectively. Results: Tubulointerstitial fibrosis was observed in DN rats, this kind of pathological changes was ameliorated in NCTD treatment group (p < 0.05). The expressions of FN, collagen IV, and TGF-b1 protein increased in the tubulointerstitial field of DN rats compared with the rats in control group. NCTD treatment could dose-dependently decrease their expression and reverse the fibrotic degree (p < 0.05). Meanwhile, the expression of CaN was detected in tubular fields of normal kidney and increased in the tubulointerstitial field in DN rats. However, NCTD downregulated its expression in a dosedependent manner (p < 0.05). Conclusions: NCTD could downregulate FN, collagen IV, and TGF-b1 expression in tubulointerstitial fields and attenuate tubulointerstitial fibrosis in the early stage of DN rats. NCTD also alleviated the expression of CaN in tubules in DN. The relationship between the role of NCTD's anti-tubulointerstitial fibrosis and its inhibition to CaN expression remains to be further elucidated.

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Section: Discussionmentioning

confidence: 99%

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Chen

Liu

et al. 2011

Renal Failure

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“…9 The CaN/ NFATc pathway was thought to play an important role in TGF-b-mediated induction of glomerular hypertrophy and FN expression, which is in agreement with other literature reporting that administration of CaN inhibitor CsA blocked accumulation of both CaN protein and CaN activity and substantially reduced ECM accumulation and hypertrophy in diabetic glomeruli. 10,11 We have found that NCTD can alleviate the expression of CaN in tubules in DN. 6 However, CaN is primarily expressed in the epithelium of proximal tubules.…”

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 93%

“…In other words, increased protein levels may be a reliable indicator of phosphatase activity. 11,13 Therefore, we only examined the expression of CaN protein in HK-2 cells. According to our study, we found that NCTD treatment inhibited the increased CaN expression in HK-2 Then, our experiments were performed using CaN targeting siRNA (a targeting catalytic subunit of CaN Aa isoform) to knock down CaN in mRNA and protein levels.…”

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 99%

“…CaN is a calcium/calmodulindependent serine/threonine phosphatase that participates in a number of cellular processes and Ca 2 þ -dependent signal transduction pathways. Gooch et al [9][10][11] demonstrated that CaN expression was increased in the diabetic kidney and played an important role in the progression of glomerulosclerosis in DN. In addition, inhibition of CaN by cyclosporine (CsA) could reduce glomerular hypertrophy and block extracellular matrix (ECM) accumulation, such as fibronectin (FN), collagen IV (ColIV), and so on, in glomuruli.…”

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confidence: 99%

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Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

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“…Calcineurin, a ubiquitously expressed calcium-/calmodulin-dependent serine-threonine phosphatase, has been shown to play a role in the context of TAL function. [6][7][8][9][10][11] Calcineurin inhibitors are widely used as immunosuppressive drugs and have undisputed benefits in decreasing rejection rates after transplantation, but also have major side effects including hypertension. Their systemic effects on the sympathetic nervous system or the renin-angiotensin-aldosterone axis have been described, but much less information is known about the cellular mechanisms of calcineurin-dependent regulation of renal transporters.…”

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confidence: 99%

Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl− Cotransporter

Borschewski

Himmerkus

Boldt

et al. 2016

Journal of the American Society of Nephrology

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The furosemide-sensitive Na + -K + -2Cl 2 -cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin Ab isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with Atype repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin Ab in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin Ab. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Ab and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Ab and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors. The furosemide-sensitive renal Na + -K + -2Cl 2 -cotransporter (NKCC2) mediates the transepithelial NaCl reabsorption in the thick ascending limb (TAL) and plays an essential role in the urinary concentration and volume regulation. 1 The transport activity of NKCC2 depends on its phosphorylation at several N-terminal, conserved threonine and serine residues, including T96, T101, and T114. 2,3 These threonines have been identified as targets for the two closely related STE20-like kinases, SPAK (SPS-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), 4,5 whereas much less information is known on the identity of the respective phosphatases. Calcineurin, a ubiquitously expressed calcium-/calmodulin-

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An emerging role for calcineurin Aα in the development and function of the kidney

Cited by 37 publications

References 49 publications

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl− Cotransporter

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