Developmental expression of ACE2 in the SHR kidney: A role in hypertension?

Abstract

The abnormal development of the intrarenal renin-angiotensin system (RAS) is thought contribute to adult-onset hypertension in the spontaneously hypertensive rat (SHR). Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with complementary actions to that of ACE. Recent studies have shown that ACE2 expression is reduced in the adult SHR. However, its regulation in pre-hypertensive animals is unknown. In this study, we examine the developmental expression of ACE2 in the rodent kidney and its temporal expression, as it relates to the development of hypertension in the SHR model. Kidneys from SHR and normotensive Wistar Kyoto (WKY) rats (n=8-12/group) at birth, 6 weeks of age, and adulthood (80 days) were examined. Gene expression and activity of ACE2 were determined by real-time reverse transcription-polymerase chain reaction and quenched fluorescence assays, respectively. Renal expression was localized by in situ hybridization and immunohistochemistry. The expression and ACE2 activity are significantly increased in the SHR kidney at birth. With the onset of hypertension, the tubular expression of ACE2 falls in SHR compared to WKY and remains reduced in the adult SHR kidney. Glomerular expression is paradoxically increased in the SHR glomerulus. The overall developmental pattern of ACE2 expression in the SHR kidney is also modified, with declining expression over the course of renal development. The developmental pattern of ACE2 expression in the SHR kidney is altered before the onset of hypertension, consistent with the key role of the RAS in the pathogenesis of adult-onset hypertension. Further research is required to distinguish the contribution of these changes to the development and progression of hypertension in this model.

Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy

“…2 This is consistent with the findings in animal models of hypertension, 18,19 although renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27 rats. 20 Similarly, in diabetic nephropathy, while upregulation of Ace2 is noted in the diabetic kidney in mice 8,10,21,22 and in humans, 23 downregulation of Aces is also reported.…”

Physiology of Kidney Renin

“…The increased renal ANG-(1-7) levels and renal expression of ACE2 have been found during pregnancy (88,410) and in response to ACE inhibition or ANG-II-AT 1 receptor antagonism (404,876). Renal ACE2 expression was found to be lower in adult SHR compared with age-matched WKY rats during lipopolysaccharide-induced acute renal failure and in several models of diabetic kidney injury (287,875,876,974,988). Several findings have suggested a protective role for the ACE2-ANG-(1-7)-Mas axis during diabetic nephropathy: 1) ACE2 gene deletion and pharmacological ACE2 inhibition with the ACE2 inhibitor MLN-4760 worsen the development of glomerular injury in diabetic mice (819,957), 2) treatment with ANG- (1-7) or the Mas receptor agonist AVE0991 ameliorates diabetes-induced renal and cardiovascular dysfunction (69,70,210), 3) attenuation of diabetic renal injury by ACE inhibition is paralleled by the increased ACE2 expression (876), and 4) increased ACE2 expression in streptozotocin-induced diabetic mice has been reported (960).…”

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27

“…25 Similarly, in adult SHR and WKY rats, ACE2 mRNA and protein was present in proximal tubuli and large vessels with weak distal tubular and glomerular presence using the initial rabbit polyclonal anti-ACE2. 26 Considering these between-laboratory discrepancies, in the current study we took great care to rigorously test validity and reproducibility of our immunohistochemistry data. To this purpose we tested different antibodies, and moreover, we reproduced the findings on paraffin as well as frozen sections.…”