AMPK signalling: Implications for podocyte biology in diabetic nephropathy

Abstract

Diabetic nephropathy is a major long-term complication of diabetes mellitus and one of the most common causes of end-stage renal disease. Thickening of the glomerular basement membrane, glomerular cell hypertrophy and podocyte loss are among the main pathological changes that occur during diabetic nephropathy, resulting in proteinuria. Injury to podocytes, which are a crucial component of the glomerular filtration barrier, seems to play a key role in the development of diabetic nephropathy. Recent studies have suggested that dysregulation of AMPactivated kinase protein, which is an essential cellular energy sensor, may play a fundamental role in this process. The purpose of this review is to highlight the molecular mechanisms associated with AMP-activated protein kinase (AMPK) in podocytes that are involved in the pathogenesis of diabetic nephropathy.

Interplay of adenosine monophosphate‐activated protein kinase/sirtuin‐1 activation and sodium influx inhibition mediates the renal benefits of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: A novel conceptual framework

“…Importantly, AMPK activity is impaired in the diabetic kidney, and this derangement contributes to the development of nephropathy (Figure ); activation of AMPK enhances the kidney's response to oxidative stress, thus preserving podocyte and renal tubular structure and glomerular function . Similarly, SIRT1 signalling is depressed in diabetic chronic kidney disease, but podocyte‐specific overexpression of SIRT1 ameliorates glomerular and renal tubulointerstitial injury in experimental models of diabetic nephropathy .…”

Salidroside ameliorates diabetic nephropathy in rats by activating renal AMPK/SIRT1 signaling pathway

“…In contrast, the STZ‐induced rats’ model is widely used to study the early changes in DN and characterized by severe hyperglycemia, hypoinsulinemia, and weight loss, possibly due to the increased catabolic effects of insulin deficiency, volume depletion, and osmotic diuresis (Kitada, Ogura, & Koya, ; Qiao, Gao, Wang, Wang, & Cui, ). In diabetic animal and individuals, the early clinical manifestations of the DN involve increased hyperfiltration, glomerular filtration rate (GFR), and microalbuminuria, whereas the end‐stage of the disease is characterized by severing glomerular damage, proteinuria, macroalbuminuria, oxidative stress, interstitial fibrosis, apoptosis, and impaired kidney function (Ding & Choi, ; Hayashi et al, ; Kitada et al, , ; Mima et al, ; Qiao et al, ; Reidy, Kang, Hostetter, & Susztak, ; Szrejder & Piwkowska, ; Yao, Zhang, & Chen, ).…”

“…(Kitada, Ogura, & Koya, 2016;Qiao, Gao, Wang, Wang, & Cui, 2017). In diabetic animal and individuals, the early clinical manifestations of the DN involve increased hyperfiltration, glomerular filtration rate (GFR), and microalbuminuria, whereas the end-stage of the disease is characterized by severing glomerular damage, proteinuria, macroalbuminuria, oxidative stress, interstitial fibrosis, apoptosis, and impaired kidney function (Ding & Choi, 2014;Hayashi et al, 2001;Kitada et al, 2003Kitada et al, , 2016Mima et al, 2008;Qiao et al, 2017;Reidy, Kang, Hostetter, & Susztak, 2014;Szrejder & Piwkowska, 2019;Yao, Zhang, & Chen, 2016).…”

“…(Bandyopadhyay et al, ; Declèves et al, ; Lagouge et al, ; Lee et al, ; Xu et al, , ). Within this view, it was shown that the nephroprotective effect of AMPK is mediated by regulation of several downstream targets including SIRT1, mTOR, PGC‐1α, NAD(P)H oxidase, ERK1/2, Akt, TGF‐β1 (Szrejder & Piwkowska, ).…”

“…Interestingly, AMPK levels and activities were significantly suppressed in the kidneys of diabetic patients and animals and were positively correlated with the severity of the degree of the DN, renal damage, and the clinical symptoms (Bandyopadhyay, Yu, Ofrecio, & Olefsky, 2006;Declèves, Mathew, Cunard, & Sharma, 2011;Eid et al, 2010;Lee et al, 2007;Rogacka, Piwkowska, Audzeyenka, Angielski, & Jankowski, 2014;Rogacka et al, 2018;Xu et al, 2012;Vitale, Mercuro, Silvestri, Fini, & Rosano, 2003). However, pharmacological activation of AMPK improved renal function, and attenuated the clinical-pathological features of DN in patients and experimental animals through reducing ROS levels, stimulating fatty acids oxidation, and inhibition of cellular inflammation, fibrosis, and apoptosis (Szrejder & Piwkowska, 2019). (Bandyopadhyay et al, 2006;Declèves et al, 2011;Lagouge et al, 2006;Lee et al, 2007;Xu et al, 2012Xu et al, , 2019.…”