Mechanism Of The Transformation Of Acute Kidney Injury To Chronic Kidney Disease

OBJECTIVE: The transformation of acute kidney injury(AKI)to chronic kidney disease(CKD)is a key factor affecting the long-term prognosis of patients,and it is also an urgent problem to be solved in nephrology.This study explored the mechanisms of AKI-CKD transformation from three perspectives: bioinformatics,molecular biology and clinical retrospective studies.METHODS: We collected AKI and CKD related samples in the NCBI GEO database,used the WGCNA package to perform gene co-expression analysis,identified the hub genes involved in CKD,and exploed the relationship between cystein-rich proteins 61(CCN1)and other hub genes.The expressions of CCN1 and EMT related genes in rat kidney were detected by real-time PCR and Western blotting,respectively.The hypoxia-reoxygenation injury cell model and CCN1(D125A)mutant cells were constructed and the effects of CCN1(D125A)on EMT were studied using si RNA and overexpression plasmids.Finally,a total of 71,041 inpatients were enrolled in the study and follow-up for 5-63 months.The relationship between renal injury and prognosis during hospitalization was observed.RESULTS: Compared with normal kidney tissue,CCN1 gene was down-regulated in hypertensive nephropathy,minimally pathological nephropathy,membranous nephropathy,lupus nephritis,focal segmental glomurular sclerosis;Co-expression analysis showed that the CCN1 gene is a hub gene involved in CKD,and MAFF,JUN,KLF6,ATF3,and JUNB are highly correlated with the CCN1.The rat I/R model showed that CCN1 was mainly expressed in renal tubular epithelial cells,and the expression of Cyr61 was up-regulated at 2h after I/R and continued for 7 days.In the cell,CCN1 overexpression can alleviate cell damage after I/R;on the contrary,inhibition of CCN1 expression up-regulates early inflammatory factors and apoptosis-related genes in hypoxiareoxygenation;CCN1(D125A)overexpression down-regulated early inflammatory factors and apoptosis-related genes in hypoxia-reoxygenation,which proves that CCN1(D125A)alleviate cell damage on early phase after injury.In TGF-β-induced cell,overexpression of CCN1 up-regulates α-SMA,Vimentin,Col3α1,and Snail,down-regulating E-cadherin,thereby aggravating renal tubular epithelial epithelial-mesenchymal transformation(EMT);conversely,Inhibition CCN1 attenuates EMT;CCN1(D125A)also attenuates renal tubular epithelial EMT,demonstrating that CCN1(D125A)attenuates TGF-β-induced renal tubular epithelial EMT.Moreover,A total of 16,098 patients(22.66%)had clinical renal impairment,of which 5,895(8.30%)were transient AKI patients,4,580(6.44%)subacute AKI patients,and 5,623(7.91%)patients with persistent AKI.Patients with persistent AKI had a higher hospital mortality rate(16.59%),while transient AKI(3.82%)and subacute AKI(2.12%)had lower mortality rates.The proportion of persistent AKI progression to CKD was as high as 8.95%,compared with 7.29% for subacute AKK and 5.48% for transient AKI(P < 0.05).There is a close relationship between acute/subacute renal impairment and long-term survival: the risk of death changes according to the stage of AKI and AKD(P trend <0.05),while persistent AKI is associated with higher risk-related long-term mortality(HR)4.51,4.32-4.71,P < 0.05)compared to subacute AKD(HR 2.25,2.13-2.39,P < 0.05)and transient AKI(HR 1.18,1.09-1.26,P < 0.05).CONCLUSION: CCN1 is involved in the progression of acute kidney injury to chronic kidney disease,and CCN1(D125A)may be a potential therapeutic target for renal fibrosis.