Background/Aims: Neutral endopeptidase (NEP) inhibition attenuates renal damage in the diabetic kidney, but little is known about the mechanisms of this renoprotective effect. Methods: We examined the interaction between angiotensin II (Ang II) and atrial natriuretic peptide (ANP) under low (5 mM) and high (30 mM) glucose conditions, on cell proliferation and extracellular matrix (ECM) synthesis in renomedullary interstitial cells (RMICs) derived from wild-type (WT) and NEP-deficient (NEP) mice. Results: Under high glucose conditions, Ang II (10–6M) increased cell proliferation (control, 174.3 ± 16.9; Ang II, 846.3 ± 91.0 cpm/well) and ECM synthesis (control, 22.3 ± 3.1; Ang II, 79.0 ± 9.6 cpm/cell) in RMICs derived from WT and NEP mice to a similar extent. ANP (10–7M) reduced Ang II-induced cell proliferation and ECM synthesis in RMICs derived from both strains, but more efficiently in RMICs derived from NEPmice. The Ang II-induced cell proliferation and ECM synthesis was attenuated with AT1 receptor blockade, but more efficiently in RMICs-derived NEP mice. Conclusions: This data shows that ANP and AT1 receptor blockade attenuate Ang II-induced RMIC proliferation and ECM synthesis more efficiently in the absence of NEP. These results support the concept that NEP inhibition is beneficial in attenuating abnormal cell growth and ECM metabolism associated with diabetic nephropathy.

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