Currently,
diabetic nephropathy (DN) is the most common cause of end-stage renal disease
(ESRD) worldwide, and approximately 40% of patients require renal replacement
therapy. Early identification of patients who are prone to develop renal
complications would be an important step for their better management during the
clinical course of this disease process (Parving et al., 2001)

Early stages of DN are characterized by
hyperfiltration, nephron enlargement and mesangial cell hypertrophy, which
later on progress to glomerulosclerosis (Satchell et al., 2008).

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Microalbuminuria has been the standard method for diagnosis of early stages
of DN; however, this method has some drawbacks. Microalbuminuria can develop
when advanced changes have already set in as assessed by renal biopsy
examination. Also, the immunoassay that measures microalbuminuria can only
detect the immunoreactive form of albumin, and its nonimmunoreactive forms are
undetectable by this method (Liu et al., 2011).

MicroRNAs
comprise 21 to 23 nucleotides, and bind to the 3?-untranslated regions (UTRs)
of their target mRNAs in a stable manner. Micro RNAs modulate a wide range of
biological functions, including oncogenesis, apoptosis, cardiac development and
insulin secretion (Chen et al., 2012). 

Upregulation
of several miRNAs can occur in diabetic kidney. These miRNAs bind to the 3’UTR
of renoprotective genes leading to their decreased expression. And in turn,
these upregulated miRNAs contribute to the pathogenesis of DN (Hao et al.,
2014).

Several
key factors are overexpressed in DN, such as TGF-?2, COL1, COL4, and NADPH
oxidase subunit 4 (NOX4).These DN-inducing factors can result in ECM
accumulation, renal fibrosis, and oxidative stress, all of which contribute to
the pathogenesis of DN. Furthermore, these factors are also targets for several
miRNAs that are downregulated in DN. Therefore, it is reasonable that these
downregulated miRNAs are DN inhibiting miRNAs which lead to the decrease of
these DN inducing factors (Hao et al., 2014).

Under
diabetic conditions, miR-216a was up regulated, followed by the inhibition of Y
box binding protein 1 which led to increased expression of TGF-? stimulated
clone 22, eventually resulting in high production of COL1?2 in MMCs (Kato et al., 2010).

MicroRNA-21 (miR-21) is considered a profibrotic microRNA; the
exact mechanism of how miR-21 participates in diabetic renal injury may be
related to: The activation of TGF-? signaling during diabetic
conditions and phosphatase and tensin homolog (PTEN) which is one of potential
targets of miR-21 and a negative regulator of epithelial-to-mesenchymal
transition. Suppression
of PTEN by miR-21 is shown to induce phosphatidylinositide 3-kinases (PI3K) and
Akt activity, and subsequently induces metalloproteinase-2 (MMP-2) expression
which control ECM turnover during fibrosis. Consequently, upregulation of Akt
pathway could be another mechanism for miR-21 to contribute in diabetic kidney
injury. The reciprocal regulation of PTEN levels and Akt1 substrate activity by
miR-21 mediates critical pathologic features of diabetic kidney disease (Li
et al., 2014).

MicroRNA-377 (miR-377) induces
fibronectin (extracellular cellular matrix protein) expression in MCs through
the downregulation of manganese superoxide dismutase and p21-activated kinase. Fibronectin is not a direct target of miR-377;
however, miR-377 first targets the expression of protein-activated kinase 1
(PAK1) and  manganese superoxide
dismutase (MnSOD), which lead to elevated fibronectin expression and hence
contribute to DN (Kantharidis et al., 2011).

MicroRNA-93 (miR-93) is a key
regulator of vascular endothelial growth factor (VEGF) signaling in the
kidneys. It has a modulatory effect on VEGF expression and its downstream
signaling, which may play a role in the pathogenesis of diabetic nephropathy. Since
VEGF targets collagen IV and fibronectin, the repression of miR-93 during
diabetic kidney disease may lead to the production of collagen and fibronectin
that are known to increase in DN (Li
et al., 2014).

MicroRNA 25 (miR-25) level
was significantly reduced both in kidneys from diabetic rats and in high
glucose-treated mesangial cells, accompanied by the increases in NOX4 (NADPH
oxidase subunit 4) expression levels. An inhibitor ofmiR-25 effectively
increased NOX4 levels. Luciferase assays showed that miR-25 directly bound to
the 3’UTR of NOX4 mRNA. These data indicate that miR-25 may be a DN-protective
molecule through inhibiting NOX4 (Fu et al., 2010).

Objective:

The aim of the current work was to study differential expressions
of miR-21, miR-93, miR-216a, miR-25 and miR-377 and their possible underlying
role in the development of nephropathy in patients with type 1 diabetic.

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