Abstract
Alteration in renin‐angiotensin system (RAS) has been implicated in the pathophysiology of diabetic kidney disease (DKD). The deleterious actions of angiotensin II (Ang II) could be antagonized by the formation of Ang‐(1–7), generated by the actions of angiotensin‐converting enzyme 2 (ACE2) and neprilysin (NEP). NEP degrades several peptides, including natriuretic peptides, bradykinin, amyloid beta, and Ang I. Although combination of Ang II receptor and NEP inhibitor treatment benefits patients with heart failure, the role of NEP in renal pathophysiology is a matter of active research. NEP pathway is a potent enzyme in Ang I to Ang‐(1–7) conversion in the kidney of ACE2‐deficient mice, suggesting a renoprotective role of NEP. The aim of the study is to test the hypothesis that chronic hyperglycemia downregulates renal NEP protein expression and activity in db/db diabetic mice and treatment with rosiglitazone normalizes hyperglycemia, renal NEP expression, and attenuates albuminuria. Mice received rosiglitazone (20 mg kg−1 day−1) for 10 weeks. Western blot analysis, immunohistochemistry, and enzyme activity revealed a significant decrease in renal and urinary NEP expression and activity in 16‐wk db/db mice compared with lean control (p < .0001). Rosiglitazone also attenuated albuminuria and increased renal and urinary NEP expressions (p < .0001). In conclusion, data support the hypothesis that diabetes decreases intrarenal NEP, which could have a pivotal role in the pathogenesis of DKD. Urinary NEP may be used as an index of intrarenal NEP status. The renoprotective effects of rosiglitazone could be mediated by upregulation of renal NEP expression and activity in db/db diabetic mice.
Highlights
Diabetic kidney disease (DKD) is one of the most frequent complications of both types of diabetes and the leading cause of end-stage renal disease (ESRD) in the Western world (Tuttle et al, 2014)
DKD is characterized by a progressive decline in the glomerular filtration rate, which is often accompanied by albuminuria and could lead to ESRD (Alicic, Rooney, & Tuttle, 2017)
A variety of mechanisms have been suggested by which angiotensin II (Ang II) can induce renal damage, the deleterious actions of Ang II can be antagonized by the formation of a vasodilator, Angiotensin (1–7), which is generated mainly by the actions of angiotensin-converting enzyme 2 (ACE2) and NEP (Donoghue et al, 2000; Rice, Thomas, Grant, Turner, & Hooper, 2004)
Summary
Diabetic kidney disease (DKD) is one of the most frequent complications of both types of diabetes and the leading cause of end-stage renal disease (ESRD) in the Western world (Tuttle et al, 2014). Renin angiotensin system (RAS) plays a central role in the control of blood pressure, and medications targeting the RAS are the most validated clinical strategies for slowing CKD progression (Campbell & Yacoub, 2015; Márquez, Riera, Pascual, & Soler, 2015) This dysregulation in the RAS system leads to increased Ang II expression along with an increase in sensitivity to its effects in the kidney. Our previous study showed that rosiglitazone treatment of type 2 diabetic db/db mice increased renal ACE2 expression levels while attenuating urinary albumin and ACE2 excretion (Chodavarapu et al, 2013) This suggests that the renoprotective effect of rosiglitazone could be mediated by the increase in RAS enzyme ACE2.
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