Elevated levels of renal and circulating Nop-7-associated 2 (NSA2) in rat and mouse models of diabetes, in mesangial cells in vitro and in patients with diabetic nephropathy

Abstract

We previously found that Nop-7-associated 2 (NSA2), which is involved in ribosomal biogenesis in yeast and is a putative cell cycle regulator in mammalian cells, is elevated in the kidney of Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. Here we tested the hypothesis that elevated NSA2 is involved in diabetic nephropathy (DN). We examined Nsa2/NSA2 expression and NSA2 production in two rodent models of diabetes, in cultured renal glomerular cells, and in diabetic patients with and without nephropathy. Patients with nephropathy who had a history of albuminuria were further divided as responders (DN-NA; DN patients normoalbuminuric at the time of this study with a history of albuminuria) and non-responders (DN-A; diabetic nephropathy patients with albuminuria) to current treatment for albuminuria. Renal Nsa2/NSA2 mRNA increased in tandem with hyperglycaemia in GK rats, in a streptozotocin-induced mouse model of diabetes, and in human mesangial cells (HMCs) grown in high glucose (p < 0.05). In the mouse model of diabetes, hyperglycaemia resulted in increased Nsa2 expression and NSA2 levels in tubular and glomerular cells and in circulating cells; this increase was normalised by diabetes treatment. Circulating NSA2 mRNA levels were elevated in patients with DN independently of body weight (BMI), glycaemic (HbA(1c)) and haemodynamic (blood pressure) control, and showed an inverse correlation with renal function (GFR, p < 0.05). NSA2 levels were the only variable that showed a significant difference between patients with albuminuria (DN-A) compared with non-albuminuric patients (DN-NA) and diabetic controls (p < 0.05), this increase being independent of all other variables, including GFR. We show for the first time that renal and circulating NSA2/NSA2 levels are increased in hyperglycaemia in experimental models of diabetes, and that circulating NSA2 is elevated in DN patients with albuminuria. Further studies will be required to assess whether NSA2 plays a role in the pathogenesis of DN.