Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy

Abstract

Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.

The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease

“…50,51 However, whole-kidney angiotensin II levels in diabetes can increase, decrease, or even remain unchanged during the progression of diabetic nephropathy. [13][14][15][16][17][18][19] As previously described, 19 there was a significant reduction of ACE expression in the kidneys of STZ-treated mice that correlates with a suppression of renal angiotensin II levels ( Figure 2). Although similar findings were described in other experimental models of diabetes, the mechanism behind this response remains elusive.…”

“…6,7 Angiotensin II is a major player in the establishment of a sodium retentive state because it activates key sodium transporters in the kidney. [8][9][10] However, the absence of systemic renin-angiotensin system (RAS) activation in diabetes, 11,12 together with studies showing that whole-kidney angiotensin II levels can increase, decrease, or remain unchanged during the progression of diabetic nephropathy, [13][14][15][16][17][18][19] suggest that other mechanisms might also be involved in controlling sodium homeostasis during diabetes.…”

Intrarenal Renin Angiotensin System Imbalance During Postnatal Life Is Associated With Increased Microvascular Density in the Mature Kidney

“…Both ACE and ACE2 activities were measured using fluorescence assays, as previously described ( Eriguchi et al, 2018 ). Briefly, whole snap-frozen kidneys were gently homogenized in 20 mM HEPES (pH 7.3) and centrifuged at 3,000 g for 15 min at 4°C.…”

Association of Urinary Biomarkers Noninvasively Forecasts The Extent of Renal Injury In The Early Diabetic Nephropathy Patients With Kidney Qi Deficiency Syndrome: A Retrospective Investigation 

“…Under the fundamental principles of TCM theory, the differentiation and treatment of DM and its complications have focused on the asthenia syndromes including the de ciency of lung, spleen (stomach) and kidney for a long time, of them, kidney asthenia is considered to be the key pathogenesis of DN, which is a well-known complication of long-standing DM [28,29,30]. However, there is no further observation on the distribution of kidney de ciency syndrome in the early DN patients.…”

“…The recent studies have demonstrated that renal tubulointersititial lesion plays a critical role along with glomerular injury in the pathogenesis of DN patients [30]. The several biomarkers indicating proximal tubular impairment have the potential to be the clinical markers for predicting renal damage extent of DN patients at the early stage.…”