Clinical Significance of Glomerular Autophagy in Evaluation of Diabetic Kidney Disease Progression

Abstract

Background

Diabetic kidney disease (DKD) is closely associated with the death or survival of resident kidney cells.

Aim

The purpose of this study was to determine the changes in renal cell survival and death in DKD and their diagnostic values in DKD progression.

Materials and Methods

This study analyzed a dataset of renal tissues from DKD patients to identify changes in genes associated with renal cell death and survival. Our findings were subsequently validated in human kidney tissues. Differential indicators of DKD patients’ clinicopathological data screened by stepwise regression and glomerular P62 protein expression were included in binary logistic regression analysis to assess the impact of these parameters on DKD progression. A receiver operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic value of P62 protein in DKD progression.

Results

Bioinformatics analysis results revealed that glomerular autophagy in DKD was more significantly altered, which was consistent with the semi-quantitative results of P62 in glomeruli. Further studies established that P62 expression was mainly increased in podocytes. Stepwise regression analysis indicated that changes in the expressions of glomerular P62 and apolipoprotein A1 (ApoA1) might be involved in the progression of DKD. However, binary logistic regression analysis results suggested that only P62 was significantly associated with DKD development. ROC curve analysis showed that the area under the curve (AUC) of P62 for the detection of DKD was 0.905.

Conclusion

Autophagy inhibition occurred in both glomeruli and tubules, and was most pronounced in glomerular podocytes. The levels of P62 protein in glomeruli, as an autophagy activity indicator, was one of the predictors of entering the stage of macroalbuminuria in DKD.

Graphical Abstract

Keywords:

• diabetic kidney disease
• autophagy
• glomerulus
• podocyte

Abbreviations

DKD, diabetic kidney disease; DEGs, differentially expressed genes; NC, normal control group; MCD, minimal change disease; ACR, albuminuria excretion rate; SD, standard deviation; AID, autoimmune disease; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; DM, diabetic mellitus; SBP, systolic blood pressure; DBP, diastolic blood pressure; BUN, blood urea nitrogen; UA, uric acid; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; 24-hUTP, 24-h urine protein quantification; 24-hUAER, 24-h urinary albumin excretion; U-TRF, urinary transferrin; U-NAG, N-acetyl β-glucosaminidase; U-IgG, urinary IgG; U-ALB, urinary albumin; U-FDP, urinary fibrinogen; U-cyc, urinary cystatin C; U-β2-MG, urinary β2 microglobulin; U-α1-MG, urinary α1-microglobulin; IFTA, interstitial fibrosis and tubular atrophy; ANOVA, one-way analysis of variance; CHO, cholesterol; LDL, low-density lipoprotein; VLDL, very low density lipoprotein; HDL, high density lipoprotein; ApoB, apolipoprotein B; ApoA1, apolipoprotein A1; ALB, albumin; U-Cr, urinary creatinine; ROC, receiver operating characteristic; TEM, transmission electron microscopy; ATGs, autophagy-related proteins; PI3K, class III phosphoinositide 3-kinase; Ub, ubiquitin; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; SQSTM1, sequestosome 1.

Data Sharing Statement

All data in this paper are derived from published sources and are acknowledged or referenced accordingly.

Ethics Approval and Consent to Participate

This study was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Anhui Medical University (Hefei, China, approval no.: 20190454). The patients provided their written informed consent to participate in this study.

Acknowledgments

The authors thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflict of interest.

Additional information

Funding

There is no funding to report.