Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice

Somineni, Hari K.; Boivin, Gregory P.; Elased, Khalid M.

doi:10.1530/joe-13-0532

Cited by 40 publications

(52 citation statements)

References 72 publications

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“…Our previous studies have shown increased shedding of enzymatically active renal ACE2 and NEP in the urine of type 2 diabetic mice (Chodavarapu et al, ; Somineni et al, ) and in type 2 diabetic patients (Gutta et al, ). We have also shown colocalization of ACE2 and ADAM 17 in the brush border of renal proximal tubules in Akita and db / db diabetic mice (Chodavarapu et al, ; Salem, Grobe, & Elased, ).…”

Section: Discussionmentioning

confidence: 91%

Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin indb/dbdiabetic mice

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 91%

Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin indb/dbdiabetic mice

et al. 2020

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“…Indeed, treatment of Akita type 1 diabetic mice with insulin normalized hyperglycemia, attenuated urinary ACE2 shedding, albuminuria, and renal ADAM17 expression (41). We have also reported that physical exercise training and/or metformin treatment of type 2 diabetic mice attenuated renal ADAM17 expression and shedding of urinary ACE2 (44). Recently, it was demonstrated that Ang II type 1 receptors promote ADAM17 mediated ACE2 shedding in hypertensive patients (54).…”

Section: Introductionmentioning

confidence: 85%

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Gutta

Grobe

Kumbaji

et al. 2018

American Journal of Physiology-Renal Physiology

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Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1-7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.

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“…Diabetes mellitus is characterized by increased blood glucose, insulin and leptin levels (Somineni et al 2014) and by impaired nitric oxide (NO) homeostasis with reduced availability of NO (Baylis 2012;Masha et al 2011;Pollock and Pollock 2011), resulting in endothelial dysfunction, a critical mediator of diabetic vasculopathy (Sena et al 2013). NO is required for S-nitrosylation, i.e.…”

Section: Introductionmentioning

confidence: 99%

Carnosine metabolism in diabetes is altered by reactive metabolites

et al. 2015

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Carnosinase 1 (CN1) contributes to diabetic nephropathy by cleaving histidine-dipeptides which scavenge reactive oxygen and carbonyl species and increase nitric oxide (NO) production. In diabetic mice renal CN1 activity is increased, the regulatory mechanisms are unknown. We therefore analysed the in vitro and in vivo regulation of CN1 activity using recombinant and human CN1, and the db/db mouse model of diabetes. Glucose, leptin and insulin did not modify recombinant and human CN1 activity in vitro, glucose did not alter renal CN1 activity of WT or db/db mice ex vivo. Reactive metabolite methylglyoxal and Fenton reagent carbonylated recombinant CN1 and doubled CN1 efficiency. NO S-nitrosylated CN1 and decreased CN1 efficiency for carnosine by 70 % (p < 0.01), but not for anserine. Both CN1 cysteine residues were nitrosylated, the cysteine at position 102 but not at position 229 regulated CN1 activities. In db/db mice, renal CN1 mRNA and protein levels were similar as in non-diabetic controls, CN1 efficiency 1.9 and 1.6 fold higher for carnosine and anserine. Renal carbonyl stress was strongly increased and NO production halved, CN1 highly carbonylated and less S-nitrosylated compared to WT mice. GSH and NO2/3 concentrations were reduced and inversely related with carnosine degradation rate (r = -0.82/-0.85). Thus, reactive metabolites of diabetes upregulate CN1 activity by post-translational modifications, and thus decrease the availability of reactive metabolite-scavenging histidine dipeptides in the kidney in a positive feedback loop. Interference with this vicious circle may represent a new therapeutic target for mitigation of DN.

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Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice

Cited by 40 publications

References 72 publications

Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin indb/dbdiabetic mice

Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin indb/dbdiabetic mice

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Carnosine metabolism in diabetes is altered by reactive metabolites

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