GSDMD Mediates Ang II-Induced Hypertensive Nephropathy by Regulating the GATA2/AQP4 Signaling Pathway

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2024 Nov 11

PMID 39525316

Authors

Xiaoxi Fan

Wenli Zhang

Ruihan Zheng

Yucong Zhang

Xianhui Lai

Jibo Han

Zimin Fang

Bingjiang Han

Weijian Huang

Bozhi Ye

Shanshan Dai

Affiliations

Soon will be listed here.

Abstract

Aim: Hypertensive nephropathy is a common complication of hypertension. However, no effective measures are currently available to prevent the progression of renal insufficiency. Gasdermin D (GSDMD) is a crucial mediator of pyroptosis that induces an excessive inflammatory response. In the present study, we aimed to determine the effect of GSDMD on the pathogenesis of hypertensive nephropathy, which may provide new insights into the treatment of hypertensive nephropathy.

Methods: C57BL/6 (wild-type, WT) and Gsdmd knockout (Gsdmd) mice were subcutaneously infused with angiotensin II (Ang II) via osmotic mini-pumps to establish a hypertensive renal injury model. Recombinant adeno-associated virus serotype 9 (AAV9) carrying GSDMD cDNA was used to overexpress GSDMD. Renal function biomarkers, histopathological changes, and inflammation and fibrosis indices were assessed. Transcriptome sequencing (RNA-seq) and cleavage under targets and mentation (CUT & Tag) experiments were performed to identify the downstream pathogenic mechanisms of GSDMD in hypertensive nephropathy.

Results: GSDMD was activated in the kidneys of mice induced by Ang II ( < 0.001). This activation was primarily observed in the renal tubular epithelial cells ( < 0.0001). GSDMD deficiency attenuated renal injury and fibrosis induced by Ang II ( < 0.0001), whereas Gsdmd overexpression promoted renal injury and fibrosis ( < 0.01). Mechanistically, GSDMD increased Ang II-induced GATA binding protein 2 (GATA2) transcription factor expression ( < 0.01). GATA2 also bound to the aquaporin 4 () promoter sequence and facilitated transcription ( < 0.001), leading to renal injury and fibrosis. Moreover, treatment with GI-Y1, an inhibitor of GSDMD, alleviated Ang II-induced renal injury and fibrosis ( < 0.01).

Conclusion: GSDMD plays an important role in the development of hypertensive nephropathy. Targeting GSDMD may be a therapeutic strategy for the treatment of hypertensive nephropathy.

References

Liu B, Tang T, Lv L, Lan H . Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int. 2018; 93(3):568-579. DOI: 10.1016/j.kint.2017.09.033. View

Long L, Zhang X, Wen Y, Li J, Wei L, Cheng Y . Qingda Granule Attenuates Angiotensin II-Induced Renal Apoptosis and Activation of the p53 Pathway. Front Pharmacol. 2022; 12:770863. PMC: 8867011. DOI: 10.3389/fphar.2021.770863. View

Kadoya H, Satoh M, Sasaki T, Taniguchi S, Takahashi M, Kashihara N . Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice. FASEB J. 2015; 29(9):3899-910. DOI: 10.1096/fj.15-271734. View

Chu C, Delic D, Alber J, Feger M, Xiong Y, Luo T . Head-to-head comparison of two SGLT-2 inhibitors on AKI outcomes in a rat ischemia-reperfusion model. Biomed Pharmacother. 2022; 153:113357. DOI: 10.1016/j.biopha.2022.113357. View

Cheng Q, Pan J, Zhou Z, Yin F, Xie H, Chen P . Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy. Acta Pharmacol Sin. 2020; 42(6):954-963. PMC: 8149386. DOI: 10.1038/s41401-020-00525-z. View

Shirasuna K, Karasawa T, Usui F, Kobayashi M, Komada T, Kimura H . NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy. Endocrinology. 2015; 156(11):4281-92. DOI: 10.1210/en.2015-1408. View

Chen X, Hocher C, Shen L, Kramer B, Hocher B . Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench. Am J Physiol Cell Physiol. 2023; 325(3):C661-C681. DOI: 10.1152/ajpcell.00177.2023. View

Humphreys B . Mechanisms of Renal Fibrosis. Annu Rev Physiol. 2017; 80:309-326. DOI: 10.1146/annurev-physiol-022516-034227. View

Yang F, Bettadapura S, Smeltzer M, Zhu H, Wang S . Pyroptosis and pyroptosis-inducing cancer drugs. Acta Pharmacol Sin. 2022; 43(10):2462-2473. PMC: 9525650. DOI: 10.1038/s41401-022-00887-6. View

10.

Wang Y, Li Y, Chen Z, Yuan Y, Su Q, Ye K . GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy. Cell Death Dis. 2022; 13(8):693. PMC: 9360039. DOI: 10.1038/s41419-022-05138-4. View

11.

Rump K, Adamzik M . Function of aquaporins in sepsis: a systematic review. Cell Biosci. 2018; 8:10. PMC: 5807818. DOI: 10.1186/s13578-018-0211-9. View

12.

Venugopal H, Hanna A, Humeres C, Frangogiannis N . Properties and Functions of Fibroblasts and Myofibroblasts in Myocardial Infarction. Cells. 2022; 11(9). PMC: 9102016. DOI: 10.3390/cells11091386. View

13.

Budi E, Schaub J, Decaris M, Turner S, Derynck R . TGF-β as a driver of fibrosis: physiological roles and therapeutic opportunities. J Pathol. 2021; 254(4):358-373. DOI: 10.1002/path.5680. View

14.

Krishnan S, Dowling J, Ling Y, Diep H, Chan C, Ferens D . Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. Br J Pharmacol. 2015; 173(4):752-65. PMC: 4742291. DOI: 10.1111/bph.13230. View

15.

Zuo Y, Chen L, Gu H, He X, Ye Z, Wang Z . GSDMD-mediated pyroptosis: a critical mechanism of diabetic nephropathy. Expert Rev Mol Med. 2021; 23:e23. PMC: 8724266. DOI: 10.1017/erm.2021.27. View

16.

Zhao L, Zhang Z, Wang P, Zhang N, Shen H, Wu H . NHH promotes Sepsis-associated Encephalopathy with the expression of AQP4 in astrocytes through the gut-brain Axis. J Neuroinflammation. 2024; 21(1):138. PMC: 11131257. DOI: 10.1186/s12974-024-03135-2. View

17.

Bonadio J, Bashiri G, Halligan P, Kegel M, Ahmed F, Wang K . Delivery technologies for therapeutic targeting of fibronectin in autoimmunity and fibrosis applications. Adv Drug Deliv Rev. 2024; 209:115303. PMC: 11111362. DOI: 10.1016/j.addr.2024.115303. View

18.

Massague J . TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012; 13(10):616-30. PMC: 4027049. DOI: 10.1038/nrm3434. View

19.

Zhang Y, Huang H, Kong Y, Xu C, Dai L, Geng X . Kidney tubular transcription co-activator, Yes-associated protein 1 (YAP), controls the expression of collecting duct aquaporins and water homeostasis. Kidney Int. 2022; 103(3):501-513. DOI: 10.1016/j.kint.2022.10.007. View

20.

Ettou S, Jung Y, Miyoshi T, Jain D, Hiratsuka K, Schumacher V . Epigenetic transcriptional reprogramming by WT1 mediates a repair response during podocyte injury. Sci Adv. 2020; 6(30):eabb5460. PMC: 7380960. DOI: 10.1126/sciadv.abb5460. View