Expression of the intrarenal angiotensin receptor and the role of renin-angiotensin system inhibitors in IgA nephropathy

Abstract

The critical role of the intrarenal renin-angiotensin system (RAS) in the development of kidney disease has been well demonstrated in animal and cell-culture experiments, but evidence from human kidney tissues is lacking. In this study, we screened 438 patients with IgA nephropathy (IgAN) and analyzed their clinical characteristics. Renal biopsy revealed the expression of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), and MAS receptor (MASR) in the tissues of 260 patients not treated with RAS inhibitors, 32 patients treated with angiotensin-converting enzyme inhibitors (ACEIs), and 89 patients treated with angiotensin receptor blockers (ARBs). The correlations in expression among these three receptors and the results of Oxford typing were analyzed, together with the ability of ACEIs and ARBs to reduce proteinuria and the effects of ARBs on AT1R and AT2R expression. The results showed significantly higher AT1R, AT2R, and MASR expression in the M1 group (mesangial score > 0.5) than in the M0 group (mesangial score < 0.5), significantly higher AT1R expression in the S1 group (presence of segmental glomerulosclerosis) than in the S0 group (absence of segmental glomerulosclerosis); AT1R expression in the C2 group (crescent formation > 25%) was significantly higher than in the C0 (crescent formation = 0) and C1 (crescent formation < 25%) groups. Patients treated with an ARB for < 6 months had significantly lower urinary protein levels than those taking these drugs for > 6 months. These findings imply that overexpression of AT1R on the mesangial cells of IgAN patients is associated with mesangial cell proliferation, glomerular segmental sclerosis, and crescent formation. In addition, long-term administration of ARB may decrease the efficacy of these medications in terms of reducing proteinuria.

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

“…Several groups have reported that RAS component expression in human kidney biopsies correlates with the presence and severity of the underlying kidney disease ( Lai et al, 1998 ; Del Prete et al, 2003 ; Mezzano et al, 2003 ; Konoshita et al, 2006 ; Kobori et al, 2007a ; Takamatsu et al, 2008 ; Ohashi et al, 2017 ; Zhang et al, 2019 ). In patients with mixed etiology kidney disease, RAS component mRNA levels were upregulated in glomeruli and tubules compared with controls ( Lai et al, 1998 ).…”

“…Greater AGT and Ang II immunoreactivity was also observed in glomeruli from pediatric patients with IgA nephropathy ( Takamatsu et al, 2008 ). Expression of the AT 1 receptor in patients with IgA nephropathy is related to disease severity and reduced by RAS inhibition ( Zhang et al, 2019 ).…”

Angiotensin II type 1 receptor blockers favorably affect renal angiotensin II and MAS receptor expression in patients with diabetic nephropathy

“…25 Our previous research also found that MAR receptor expression levels were significantly higher in the group of mesangial hypercellularity. 26 Currently, we believe that the local MAS receptor in the kidney is a protective receptor, and its expression is increased in the case of kidney damage.…”

Factors associated with the progression of mesangial lesions in IgA nephropathy: A comparative analysis of renal re-biopsies

“…The renin-angiotensin system (RAS) plays an important role in the pathophysiology of renal diseases. IgAN is characterized by local activation of the RAS and upregulated expression of the angiotensin receptor type 1 (AT1R) (3)(4)(5). New components of the RAS have been identified recently, including angiotensin (Ang)-(1-7), Mas receptor (MasR), Ang-(1-9) and alamandine (6,7).…”

“…Almost 30% of patients require dialysis or transplant within 20 years after diagnosis. Mesangial cell hyperplasia and mesangial matrix accumulation (i.e., mesangial lesions) are the main pathological lesions of IgAN, and directly cause glomerulosclerosis and, subsequently, renal failure ( 2 , 3 ).…”