Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

Abstract

Background Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. Methods We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. Results ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. Conclusions Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

Identification of key biomarkers in the tubulointerstitium of patients with focal segmental glomerulosclerosis and their relationship with immune cell infiltration using weighted gene co-expression network analysis and least absolute shrinkage and selection operator

“…Recent studies have shown that angiotensin-converting enzyme 2 (ACE2) expression is also associated with interstitial brosis and tubular atrophy in men and correlates with TGF-β1 in patients with FSGS studied by the Nephrotic Syndrome Research Network using renal tubular interstitial microarray data and clinical variables (Maksimowski et al 2021). The results of this study were consistent with those of the present study.…”

Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease

“…Although developed as a model of Alport Syndrome, studies of Col4a3 -/mice may also provide insights into the pathogenesis of a wider spectrum of kidney disease because the Col4a3 gene plays a role in both sporadic and familial FSGS as well as diabetic nephropathy [19,20]. Moreover, changes in the TI of the kidney, in particular fibrosis and tubular atrophy, correlate inversely with GFR [21,22].…”

COVID-19 Infection and Acute Kidney Injury: About 43 Cases Report Collected at the Nephrology Department of the Farah Polyclinic in Abidjan

“…Male gender is already identified as a factor associated with the occurrence of an AKI during Covid [18] [19]. One hypothesis was the overexpression of ACE2 in male subjects [20]. Androgenic hormones would also play a role in increasing the expression of ACE2 [21].…”