Abstract
BackgroundAngiotensin-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.MethodsWe 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.ResultsACE2 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.ConclusionsSex 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.
Highlights
The renin angiotensin system (RAS) plays a key role in the progression of chronic kidney disease (CKD), and blockade of the RAS is a centerpiece of the current clinical approach to the treatment, especially in CKD associated with proteinuria
Angiotensin-converting enzyme 2 (ACE2) is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS)
Multiple linear regression analysis showed that ACE2 expression was related to sex and estimated glomerular filtration rate (eGFR) but not to age or treatment with renin angiotensin system blockade
Summary
The renin angiotensin system (RAS) plays a key role in the progression of chronic kidney disease (CKD), and blockade of the RAS is a centerpiece of the current clinical approach to the treatment, especially in CKD associated with proteinuria. ACE2 plays a role in the pathogenesis of experimental kidney disease. Deletion of the gene for ACE2 leads to the development of proteinuria and focal segmental glomerulosclerosis (FSGS) in mice [7] and exacerbates diabetic kidney injury [8]. 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
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