Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy

Abstract

Aims Kidney cells in patients with diabetic nephropathy are reported to be senescent. However, the mechanisms that regulate cellular senescence in the diabetic kidney are still unknown. In the present study, we evaluated the contribution of high glucose to renal cell senescence in streptozotocin (STZ)-induced diabetic mice. Methods Non-diabetic and streptozotocin (STZ, 10 mg kg–1 day–1 for 7 days, i.p.)-induced type 1 diabetic C57BL/6 J mice and cultured human proximal tubular cells were used in this study. Results Hyperglycemia dramatically increased the renal expression of p21 but not other CDK inhibitors such as p16 and p27 at 4 weeks after STZ injection. These changes were accompanied by an increase in senescence-associated β-galactosidase staining in tubular epithelial cells. Administration of insulin at doses that maintained normoglycemia or mild hypoglycemia suppressed the changes induced by STZ. Insulin did not affect the senescent markers in non-diabetic mice. Exposure of cultured human proximal tubular cells to 25 mmol/L, but not 8 mmol/L, glucose medium increased the expression of senescence markers, which was suppressed by knock-down of p21 or sodium glucose cotransporter (SGLT) 2. Conclusions These results suggest that hyperglycemia causes tubular senescence via a SGLT2- and p21-dependent pathway in the type 1 diabetic kidney.

Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney

“…We recently reported that hyperglycemia-induced p21 plays an important role in the development of tubular cell senescence in the early phase (at week 4) of type 1 diabetes (Kitada et al, 2014). However, in contrast, it appears that the acceleration of tubular cell senescence was independent of both iron overload- and p21-dependent mechanisms in the present study (at week 28).…”

“…P21, a cyclin-dependent kinase inhibitor, plays an important role in cell senescence and the decrease in innate the function of tubular cells, resulting in increased collagen expression, tumor necrosis factor α (TNF-α) secretion and apoptosis (Fan et al, 2011; Kitada et al, 2012). We recently reported that hyperglycemia causes kidney cell senescence through a p21-dependent pathway; this phenomenon was dramatically prevented by insulin-treatment in mice and sodium-glucose transporter 2 knockdown in proximal tubular cells (Kitada et al, 2014). …”

Clinical strategies and animal models for developing senolytic agents

“…Senescent cells have been identified at sites of pathology in a number of these conditions and may have systemic effects that predispose to others. These include: 1) metabolic conditions (diabetes, obesity, metabolic syndrome, and age-related lipodystrophy (Minamino et al, 2009; Tchkonia et al, 2010)), 2) cardiovascular disorders (atherosclerosis, hypertension, heart failure, and peripheral vascular disease (Holdt et al, 2011; Kirkland, 2013a; Minamino et al, 2002; Wang et al, 2012; Westhoff et al, 2008)), 3) frailty (sarcopenia (Baker et al, 2011; Tchkonia et al, 2013)), 4) blindness (cataracts, glaucoma, macular degeneration (Baker et al, 2011; Kozlowski, 2012; Liton et al, 2005)), 5) loss of resilience (side effects shortly after or many years after chemotherapy or radiation, delayed recovery after elective surgery or acute events such as myocardial infarction (Kirkland, 2013a; Le et al, 2010; Marcoux et al, 2013; Roninson, 2003; Tchkonia et al, 2013)), 6) neurodegenerative diseases (Alzheimer's disease and “tau-opathies”, Parkinson's, “chemo brain” after, for example, cis-platinum, HIV dementia (Chinta et al, 2013; Golde et al, 2009; Kirkland, 2013a; Krull et al, 2013)), 7) bone disorders (osteoporosis, osteoarthritis, fracture non-union (Bajada et al, 2009; Chen et al, 2013; Freund et al, 2010; Price et al, 2002)), 8) lung conditions (idiopathic pulmonary fibrosis, bleomycin lung and other drug- or environmental-toxin related lung diseases, and chronic obstructive lung disease (Aoshiba et al, 2009; Barnes, 2013; Minagawa et al, 2011a; Tsuji et al, 2004; Tsuji et al, 2009)), 9) liver disease (primary biliary cirrhosis(Tabibian et al, 2014), 10) genitourinary dysfunction (age-related glomerulosclerosis, predisposition to acute tubular necrosis, diabetic renal disease, prostatic hypertrophy (Castro et al, 2003; Choi et al, 2000; Clements et al, 2013; Kirkland, 2013a; Kitada et al, 2014)), 11) skin disorders: melanocytic naevi, chronic skin ulcers (bedsores)(Gray-Schopfer et al, 2006; Vande Berg et al, 2005), 12) cancers (Campisi et al, 2007; Kirkland, 2013a; Liu et al, 2007), 13) toxin exposures and drug or radiation treatments (drugs: alkylating and other chemotherapeutic agents (Roninson, 2003), HIV protease inhibitors (Torres et al, 2014), hormones: long term growth hormone treatment (Stout et al, 2014), toxins (Welford et al, 2010), long term effects of therapeutic or accidental radiation (Marcoux et al, 2013)), 14) genetic disorders (such as progerias (Benson et al, 2010)), 15) infections (n...…”

The emerging role of cellular senescence in renal diseases

“…68 Meanwhile, kidney interstitial injury is also critical to the development of diabetic nephropathy. 69 Furthermore, several studies have demonstrated a direct link between hyperglycaemia and the induction of senescence in vitro in cultured proximal tubule cells 69 and mesangial cells 70 as well as in vivo in a mouse model of type 1 diabetes mellitus. 69 Furthermore, several studies have demonstrated a direct link between hyperglycaemia and the induction of senescence in vitro in cultured proximal tubule cells 69 and mesangial cells 70 as well as in vivo in a mouse model of type 1 diabetes mellitus.…”