Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice

Abstract

Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status.

Novel Biomarkers for Early Diagnosis and Progression of Diabetic Nephropathy

“…Urinary biomarkers could be sensitive, noninvasive and clinically useful method which is particularly attractive because urine is the easily available source. Newly reported urinary ACE2 levels were increased and correlated with albuminuria, serum creatinine and glucagon, suggesting that urinary ACE2 could be used as a biomarker for DN (Salem et al 2014), and vast similar results have been reported. But because of these kinds of studies have limitations such as small sample size, cross-sectional, short-term prospective nature and the long way from bench to bed, new molecular technologies such as transcriptomics, genetics and genomics should be further used to discover novel DN biomarkers despite the increased costs.…”

Role of Brain Angiotensin (1-7) In Chronic Hyperglycaemia Induced Nephropathy in Wistar Rats

“…19,21 Moreover, prolonged hyperglycaemia is noted to decrease the renal concentration of ACE 2 and its fragments. [22][23][24] The brain plays an important role in the regulation of peripheral activity of RAAS. 25 Brain RAS is involved in development of hypertension, heart failure and kidney failure.…”

“…54 Peripheral renin angiotensin system get disturbed in DN due to increased level of glomerular angiotensin converting enzyme (ACE) and Ang II 14 whereas the level of ACE2 get decreased in diabetic condition. 22,24 However, it has been documented that inhibition of Angiotensin type 1 receptors (AT1R) in the brain by ICV administration of ACE inhibitor or AT1 blocker is reported to increase formation of cerebral ACE 2 and Ang (1-7) and reduces the central sympathetic outflow and plasma levels of rennin and Ang II. [30][31][32]50,55,56 In our study, 2 week ICV administration of Ang (1-7) in a rat model of DN attenuated the progression of DN, as exhibits by reduced in level of serum creatinine, ratio of kidney weight to body weight, 24-hr urinary volume, blood urea nitrogen, protein in urine, serum cholesterol, serum triglyceride and increased in level of serum nitrite.…”

Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells

“…Previously, significantly decreased renal ACE2 was detected in diabetic animals and in mice with chronic kidney disease (5,10,26,27,44). However, recent studies provided evidence for increased expression of ACE2 in renal proximal tubules in kidneys of diabetic mice (6,56,57) and urine (6,38,42,52), suggesting that urinary ACE2 levels reflect renal pathophysiology. Therefore, ACE2 was proposed as a potential early biomarker of kidney disease.…”

“…Therefore, ACE2 was proposed as a potential early biomarker of kidney disease. Indeed, increased ACE2 shedding into urine has been described for diabetic mice (6,38,52) and for patients with chronic kidney disease, in diabetic renal transplant patients, and in patients with diabetic nephropathy (29,48,53).…”