Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate‐salt hypertensive uni‐nephrectomized KKA ^y mice

Abstract

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.

Prostaglandin E2 (PGE2) and Roflumilast Involvement in IPF Progression

“…That study also deducted that PGE2 could be used to reduce fibrosis in IPF. Moreover, it was recently shown that PDE4 inhibition significantly decreased CTGF, PAI-1, collagen 1A1 and fibronectin mRNA in TGFβ-stimulated human mesangial cells [47]. These results are in accordance to our results, as the IPF-CM system was previously shown to activate TGF-β signaling [15].…”

Clinical Implication of Phosphodiesterase-4-Inhibition

“…In deoxycorticosterone acetate-induced hyperglycemia, represented by a murine hypertension kidney failure model, mRNA expression was elevated for PDE4A, B and D in the kidney after three weeks [82]. Compound A, a selective PDE4-I (N-[Amino (dimethylamino)methylidene]-4-[(3aS,9bR)-8-ethoxy-7-methoxy-1,3,3a,9b-tetrahydrofuro[3, 4-c]isoquinolin-5-yl]benzamide), significantly suppressed the urinary albumin creatinine ratio, urinary KIM-1 (kidney injury molecule) and MCP-1 (monocyte chemoattractant protein) levels.…”