Abstract
Aims
Mounting evidence has shown that caveolin-1 plays a pathological role in the progression of albuminuria. Our study aimed to provide clinical evidence showing whether circulating caveolin-1 levels were associated with microalbuminuria (MAU) in women with overt diabetes mellitus in pregnancy (ODMIP).
Methods
A total of 150 pregnant women were enrolled in different groups, including 40 women with ODMIP and MAU (ODMIP + MAU), 40 women with ODMIP, and 70 women without ODMIP (Non-ODMIP). Plasma caveolin-1 levels were determined by ELISA. The presence of caveolin-1 in the human umbilical vein vascular wall was evaluated by immunohistochemical and western blot analysis, respectively. Albumin transcytosis across endothelial cells was measured using an established nonradioactive in vitro approach.
Results
Significantly increased levels of plasma caveolin-1 were detected in ODMIP + MAU women. The Pearson’s correlation analysis revealed a positive correlation between plasma caveolin-1 levels and Hemoglobin A1c (HbA1c %) as well as with MAU in the ODMIP + MAU group. Simultaneously, experimental knockdown or overexpression of caveolin-1 significantly decreased or increased the level of albumin transcytosis across both human and mouse glomerular endothelial cells (GECs), respectively.
Conclusions
Our data showed a positive association between plasma caveolin-1 levels and microalbuminuria in ODMIP + MAU.
Similar content being viewed by others
Availability of data and materials
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Abbreviations
- FITC:
-
Fluoresceine isothiocyanate
- MGECs:
-
Mouse glomerular endothelial cells
- HGECs:
-
Human glomerular endothelial cells
- HbA1c:
-
Hemoglobin A1c
- Non-ODMIP:
-
Non-overt diabetes mellitus in pregnancy
- ODMIP:
-
Overt diabetes mellitus in pregnancy
- ODMIP + MAU:
-
Overt diabetes mellitus in pregnancy with microalbuminuria
References
Simmons D (2021) Paradigm shifts in the management of diabetes in pregnancy: The importance of Type 2 diabetes and early hyperglycemia in pregnancy: The 2020 Norbert Freinkel award lecture. Diabetes Care 44:1075–1081. https://doi.org/10.2337/dci20-0055
Metzger BE, Gabbe SG, Persson B et al (2010) International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33:676–682. https://doi.org/10.2337/dc09-1848
Koning SH, van Zanden JJ, Hoogenberg K et al (2018) New diagnostic criteria for gestational diabetes mellitus and their impact on the number of diagnoses and pregnancy outcomes. Diabetologia 61:800–809. https://doi.org/10.1007/s00125-017-4506-x
Tehrani FR, Naz MSG, Bidhendi-Yarandi R et al (2022) Effect of different types of diagnostic criteria for gestational Diabetes mellitus on adverse neonatal outcomes: a systematic review, meta-analysis, and meta-regression. Diabetes Metab. J. https://doi.org/10.4093/dmj.2021.0178
(2014) Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World Health Organization Guideline. Diabetes research and clinical practice 103:341–363. https://doi.org/10.1016/j.diabres.2013.10.012
Colagiuri S, Falavigna M, Agarwal MM et al (2014) Strategies for implementing the WHO diagnostic criteria and classification of hyperglycaemia first detected in pregnancy. Diabetes Res Clin Pract 103:364–372. https://doi.org/10.1016/j.diabres.2014.02.012
Tumminia A, Milluzzo A, Cinti F et al (2018) Abnormal 1-hour post-load glycemia during pregnancy impairs post-partum metabolic status: a single-center experience. J Endocrinol Invest 41:567–573. https://doi.org/10.1007/s40618-017-0774-z
Nikolaidou B, Gkaliagkousi E, Anyfanti P et al (2020) The impact of hyperglycemia on urinary albumin excretion in recent onset diabetes mellitus type II. BMC Nephrol 21:119. https://doi.org/10.1186/s12882-020-01774-0
Wong VW, Chong S, Jalaludin B et al (2014) Urine albumin-creatinine ratio in women with gestational diabetes: its link with glycaemic status. Aust N Z J Obstet Gynaecol 54:529–533. https://doi.org/10.1111/ajo.12243
Liew A, Bavanandan S, Prasad N et al (2020) Asian pacific society of nephrology clinical practice guideline on diabetic kidney disease - executive summary. Nephrology (Carlton, Vic.) 25 Suppl 2:3–11. https://doi.org/10.1111/nep.13763
Karalliedde J, Viberti G (2004) Microalbuminuria and cardiovascular risk. Am J Hypertens 17:986–993. https://doi.org/10.1016/j.amjhyper.2004.08.010
Haraldsson B, Nyström J, Deen WM (2008) Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 88:451–487. https://doi.org/10.1152/physrev.00055.2006
Fridén V, Oveland E, Tenstad O et al (2011) The glomerular endothelial cell coat is essential for glomerular filtration. Kidney Int 79:1322–1330. https://doi.org/10.1038/ki.2011.58
Satchell S (2013) The role of the glomerular endothelium in albumin handling. Nat Rev Nephrol 9:717–725. https://doi.org/10.1038/nrneph.2013.197
Wu D, Yang X, Zheng T et al (2016) A novel mechanism of action for salidroside to alleviate diabetic albuminuria: effects on albumin transcytosis across glomerular endothelial cells. American journal of physiology. Endocrinol Metab 310:E225-237. https://doi.org/10.1152/ajpendo.00391.2015
Alphonsus CS, Rodseth RN (2014) The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia 69:777–784. https://doi.org/10.1111/anae.12661
Castrop H, Schießl IM (2017) Novel routes of albumin passage across the glomerular filtration barrier. Acta Physiol (Oxf) 219:544–553. https://doi.org/10.1111/apha.12760
Moriyama T, Sasaki K, Karasawa K et al (2017) Intracellular transcytosis of albumin in glomerular endothelial cells after endocytosis through caveolae. J Cell Physiol 232:3565–3573. https://doi.org/10.1002/jcp.25817
Hu G, Minshall RD (2009) Regulation of transendothelial permeability by Src kinase. Microvasc Res 77:21–25. https://doi.org/10.1016/j.mvr.2008.10.002
He FF, Gong Y, Li ZQ et al (2018) A new pathogenesis of albuminuria: role of transcytosis. Cell Physiol Biochem 47:1274–1286. https://doi.org/10.1159/000490223
Muley H, Fadó R, Rodríguez-Rodríguez R et al (2020) Drug uptake-based chemoresistance in breast cancer treatment. Biochem Pharmacol 177:113959. https://doi.org/10.1016/j.bcp.2020.113959
Yang C, He B, Dai W et al (2021) The role of caveolin-1 in the biofate and efficacy of anti-tumor drugs and their nano-drug delivery systems. Acta Pharmaceutica Sinica B 11:961–977. https://doi.org/10.1016/j.apsb.2020.11.020
Parat MO, Riggins GJ (2012) Caveolin-1, caveolae, and glioblastoma. Neuro Oncol 14:679–688. https://doi.org/10.1093/neuonc/nos079
Sheng Q, Li G, Liu H et al (2022) Clinical evidence for elevated levels of caveolin-1 in circulation of patients with diabetic foot ulcers. Wound Repair Regener 30:107–116. https://doi.org/10.1111/wrr.12983
Zhang D, Gava AL, Van Krieken R et al (2019) The caveolin-1 regulated protein follistatin protects against diabetic kidney disease. Kidney Int 96:1134–1149. https://doi.org/10.1016/j.kint.2019.05.032
Chatterjee M, Ben-Josef E, Robb R et al (2017) Caveolae-mediated endocytosis is critical for albumin cellular uptake and response to albumin-bound chemotherapy. Can Res 77:5925–5937. https://doi.org/10.1158/0008-5472.Can-17-0604
Van Krieken R, Krepinsky JC (2017) Caveolin-1 in the pathogenesis of diabetic nephropathy: potential therapeutic target? Curr DiabRep 17:19. https://doi.org/10.1007/s11892-017-0844-9
Immanuel J, Eagleton C, Baker J et al (2021) Pregnancy outcomes among multi-ethnic women with different degrees of hyperglycaemia during pregnancy in an urban New Zealand population and their association with postnatal HbA1c uptake. Aust N Z J Obstet Gynaecol 61:69–77. https://doi.org/10.1111/ajo.13231
Yuen DA, Stead BE, Zhang Y et al (2012) eNOS deficiency predisposes podocytes to injury in diabetes. J Am Soc Nephrol 23:1810–1823. https://doi.org/10.1681/ASN.2011121170
Cankova Z, Huang JD, Kruth HS et al (2011) Passage of low-density lipoproteins through Bruch’s membrane and choroid. Exp Eye Res 93:947–955. https://doi.org/10.1016/j.exer.2011.10.016
Bai X, Yang X, Jia X et al (2020) CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis. Autophagy 16:1111–1129. https://doi.org/10.1080/15548627.2019.1659613
Zhu T, Meng Q, Ji J et al (2017) TLR4 and Caveolin-1 in monocytes are associated with inflammatory conditions in diabetic neuropathy. Clin Transl Sci 10:178–184. https://doi.org/10.1111/cts.12434
Wang G, Cui W, Chen S et al (2021) Metformin alleviates high glucose-induced ER stress and inflammation by inhibiting the interaction between caveolin1 and AMPKα in rat astrocytes. Biochem Biophys Res Commun 534:908–913. https://doi.org/10.1016/j.bbrc.2020.10.075
Wu J, Zhou SL, Pi LH et al (2017) High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: a potential molecular mechanism for diabetes-induced cognitive dysfunction. Oncotarget 8:40843–40856. https://doi.org/10.18632/oncotarget.17257
Thipsawat S (2021) Early detection of diabetic nephropathy in patient with type 2 diabetes mellitus: a review of the literature. Diab Vasc Dis Res 18:14791641211058856. https://doi.org/10.1177/14791641211058856
Perkins BA, Bebu I, de Boer IH et al (2019) Risk factors for kidney disease in Type 1 diabetes. Diabetes Care 42:883–890. https://doi.org/10.2337/dc18-2062
Haddad D, Al Madhoun A, Nizam R et al (2020) Role of Caveolin-1 in diabetes and its complications. Oxid Med Cell Longev 2020:9761539. https://doi.org/10.1155/2020/9761539
Moriyama T, Tsuruta Y, Shimizu A et al (2011) The significance of caveolae in the glomeruli in glomerular disease. J Clin Pathol 64:504–509. https://doi.org/10.1136/jcp.2010.087023
Moriyama T, Karasawa K, Hasegawa F et al (2019) Sertraline reduces albuminuria by interfering with Caveolae-mediated endocytosis through glomerular endothelial and epithelial cells. Am J Nephrol 50:444–453. https://doi.org/10.1159/000503917
Florkowski CM (2008) Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests. Clin Biochem Rev 29(Suppl 1):S83-S87
Funding
This study was supported by the National Natural Science Foundation of China (82000425 and 82070862).
Author information
Authors and Affiliations
Contributions
X.B. conceived and designed the study. Y.S., Y.X., and X.B. carried out the experiments. X.B. analyzed the research data and wrote the manuscript. S.J. devised to establish the transcytosis model, interpreted the ROC curve data, and revised the manuscript. Y.S. and Y.X. contributed equally to this work. Y.S. and Y.X. are co-first authors. X.B. and S.J. are the guarantors of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors have nothing to disclose. The authors declare that they have no conflicts of interest.
Ethics approval and consent to participate
This study was conducted according to the Declaration of Helsinki and was approved by Huazhong University of Science and Technology (Approval IRBID: [2022] IEC RYJ 028). Written informed consent was obtained from each patient.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Shu, Y., Xiong, Y., Song, Y. et al. Positive association between circulating Caveolin-1 and microalbuminuria in overt diabetes mellitus in pregnancy. J Endocrinol Invest 47, 201–212 (2024). https://doi.org/10.1007/s40618-023-02137-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-023-02137-w