Research Article: Ramipril can alleviate the accumulation of renal mesangial matrix in rats with diabetic nephropathy by inhibiting insulin-like growth factor-11

Date Published: February 14, 2019

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em

Author(s): Wei Ren, Chen Zhao, Yan Wang, Yuan Fang, Zhenzhen Huang, Wei Chen, Lihua Wang, Wen Hu, Ke Wang, Lijun Ni.


To investigate the impact of Ramipril (RAM) on the expressions of
insulin-like growth factor-1 (IGF-1) and renal mesangial matrix (RMM) in
rats with diabetic nephropathy (DN).

The Sprague Dawley rats were divided into normal control (NC) group (n =
12), DN group (n = 11), and DN+RAM group (n = 12). The ratio of renal weight
to body weight (RBT), fasting blood glucose (FBG), HbA1c, 24-h urine protein
(TPU), blood urea nitrogen (BUN), creatinine (Cr), renal pathological
changes, the levels of IGF-1, fibronectin (FN), type IV collagen (Col-IV),
and matrix metalloproteinases (MMP)-2 were compared among the groups.

Compared with NC group, the RBT, FBG, HbA1c, TPU, BUN, Cr, and RMM in DN
group were significantly increased (P < 0.05), the IGF-1, FN, and Col-IV were significantly upregulated (P < 0.05), while MMP was significantly downregulated (P < 0.05). Compared with DN group, the indexes except for the FBG and HbA1c in DN+RAM group were significantly improved (P < 0.05), among which IGF-1 exhibited significant positive correlation with TPU(r=0.937), FN(r=0.896) and Col-IV(r=0.871), while significant negative correlation with MMP-2 (r=-0.826) (P<0.05). RAM may protect the kidneys by suppressing IGF-1 and mitigating the accumulation of RMM.

Partial Text

Diabetes mellitus (DM) is a chronic metabolic disease severely threatening the
public’s health. It is involved in many organs of the body with high mortality and
morbidity. One epidemiological investigation has shown that the prevalence of DM in
Chinese adults in 2013 was increased to 11.6%, and the total number had reached 114
million1,2. Diabetic nephropathy (DN) is a common chronic complication of DM as well as
the leading cause of end stage renal failure (ESRD) and death3,4. The characteristic pathological changes of DN are glomerular mesangial cell
hypertrophy, basement membrane thickening, and excessive accumulation of
extracellular matrix, which thus cause progressive glomerular sclerosis. The
pathogenesis is complex and has not been fully elucidated yet5,6. Existing studies have shown that the accumulation of mesangial
extracellular matrix is one of the most prominent pathological changes in DN, and
it’s also the important pathological basis for nodular or diffuse glomerulosclerosis
and the occurrence and development of DN7,8. Therefore, exploring the mechanism of mesangial extracellular matrix
accumulation and new therapeutic targets have become hot research spots.

This study was carried out in strict accordance with the recommendations in the
Guide for the Care and Use of Laboratory Animals of the National Institutes of
Health. The animal use protocol has been reviewed and approved by the Institutional
Animal Care and Use Committee (IACUC) of Anhui Medical University.

The pathogenesis of DN is complex and may be related to gene, glucose metabolic
disorder, hemodynamic disturbance, insulin resistance, oxidative stress, or
immunoinflammatory reaction, and it has been a hot spot all over the world. The main
pathological features of DN are glomerular mesangial cell hypertrophy, basement
membrane thickening, mesangial cell proliferation, and excessive accumulation of
extracellular matrix, as well as glomerular and renal tubulointerstitial fibrosis in
late stages, which eventually leads to renal failure. The excessive accumulation of
extracellular matrix in the mesangial area is the most important pathologic feature
of DN, and it is the common result of the increase of FN, Col-IV, and laminin (LN)
and the decrease of MMP-26. MMP-2 is a zinc-dependent matrix metalloproteinase, as the main gelatinase
that degrades FN, Col-IV, and LN in the mesangium, it can reduce the accumulation of
extracellular matrix and plays an important role in the occurrence and development
of DN15,16.




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