1. Introduction
Diabetic kidney disease (DKD) is the leading cause of end-stage renal
disease in the United States (Reidy, Kang, Hostetter & Susztak, 2014).
Although chronic hyperglycemia
has been considered as the main culprit for microvascular complications
of diabetes, the underlying mechanism of DKD remains poorly understood
(Rossello & Yellon, 2017). Current strategies show limited efficacy in
preventing the progression of DKD, such as control of blood pressure and
glucose levels along with administration of angiotensin-receptor
blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEI)
(Gregg et al., 2014). These findings remind us that there may be some
unknown mechanisms that involved in the development of DKD.
Emerging evidence has showed that
the proximal tubule plays a
pivotal role in the initiation and progression of DKD (Russo, Sandoval,
Campos, Molitoris, Comper & Brown, 2009). The kidney, especially the
proximal tubules is high-energy demanded and rich of mitochondria
(Weinberg, Venkatachalam, Roeser & Nissim, 2000). Recent studies have
confirmed the involvement of mitochondria fission in the development of
DKD (Bhargava & Schnellmann, 2017). As a result of loss of
mitochondrial membrane potential, fission is induced by the
translocation of dynamin-related protein 1 (DRP1) from the cytosol to
the mitochondrial outer membrane (Bhargava & Schnellmann, 2017). Bunch
of studies have suggested the posttranscriptional phosphorylation of
Drp1 as a key modulator of mitochondrial fission.
Phosphorylation at Serine-616 is
associated with increased activity of DRP1 (pro-fission). On the
contrary, phosphorylation at Serine-637 shows opposite effect
(anti-fission) (Chang & Blackstone, 2007). However, the underlying
molecular mechanism for mitochondrial dynamics regulation in DN are not
fully understood.
Recent studies showed that metformin and 5-aminoimidazole-4-
carboxamide-1-riboside (AICAR) could attenuate DKD in vitro and in vivo
experiments by activating Adenosine 5’-monophosphate activated protein
kinase-(AMPK) (Lee et al., 2013; Takiyama et al., 2011). Meanwhile, AMPK
was reported as a regulator of mitochondrial homeostasis via inhibiting
mitochondrial fission in several studies (Toyama et al., 2016; Wang et
al., 2017). So, we hypothesize that the renal protective effect of AMPK
was correlated with its anti-fission function, but the underling
mechanisms remained unclear.
Phosphoglycerate mutase family member 5 (PGAM5) plays an important role
in the initiation of mitochondrial fission by dephosphorylating the
DRP1S637 and promoting DRP1 mitochondrial translocation (Wang, Jiang,
Chen, Du & Wang, 2012). PGAM5 is
a mitochondria-resident protein. Bunch of studies have confirmed its
involvement in the development of
Parkinson’s disease
(Lu et al., 2014), acute kidney injury (Gu et al., 2019) and liver
inflammation (Kang et al., 2015). However, whether the PGAM5
participates in the development of DKD and if the AMPK involved in the
regulation of PGAM5 in DKD are unknown.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors were recently
developed as a class of anti-diabetic agents to promote urine glucose
excretion without changing the secretion of insulin (Steven et al.,
2017; Zinman, Lachin & Inzucchi, 2016). Clinical trials have observed
encouraging effect of SGLT2 inhibitors on improving DKD outcomes (Neal,
Perkovic & Matthews, 2017; Perkovic et al., 2019; Wanner, Inzucchi &
Zinman, 2016), though the underlining mechanisms are remained
controversial. Recent evidence
showed that the SGLT2 inhibitors, Empagliflozin (Empa), can activate
AMPK and alleviate the mitochondrial fission in diabetic myocardial
microvascular endothelial cell through recovering the
decreased phosphorylation of DRP1
at the Serine-637 (Zhou, Wang, Zhu, Hu, Chen & Ren, 2018), suggesting
the possible involvement of PGAM5. Since the proximal tubules are the
main site of SGLT2 expression and rich of mitochondria (Washburn &
Poucher, 2013), we hypothesize that the Empa could fulfill its renal
protective effect by alleviating mitochondrial fission via prompting the
AMPK phosphorylation in DKD and the PGAM5 may be involved in this
procedure.