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Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate‐salt hypertensive uni‐nephrectomized KKA y mice
Author(s) -
Nio Yasunori,
Ookawara Mitsugi,
Yamasaki Midori,
Hanauer Guido,
Tohyama Kimio,
Shibata Sachio,
Sano Tomoya,
Shimizu Fumi,
Anayama Hisashi,
Hazama Masatoshi,
Matsuo Takanori
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001084r
Subject(s) - medicine , endocrinology , renal hypertrophy , sildenafil , kidney , creatinine , angiotensin ii , diabetic nephropathy , receptor
Diabetic nephropathy (DN) is a leading cause of end‐stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long‐term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)‐salt hypertensive uni‐nephrectomized (UNx) KKA y mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule‐1, and monocyte chemoattractant protein‐1 levels, as well as that of renal pro‐fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor‐beta (TGF‐β). Moreover, compound A significantly suppressed TGF‐β‐induced pro‐fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.