Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy

Abstract

We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old wild-type (WT) and PAPP-A knock-out (KO) mice. Renal histopathology was evaluated after four months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman’s capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration as diabetic WT mice indicating that these changes were predominantly age-related. However, thickened Bowman’s capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic PAPP-A KO mice had significantly reduced or no evidence of changes in Bowman’s capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT compared to PAPP-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.

Pregnancy-associated plasma protein-A is a stronger predictor for adverse cardiovascular outcomes after acute coronary syndrome in type-2 diabetes mellitus

“…PAPP-A was reported to be higher in T2DM than healthy controls in 2 studies [15, 16], appeared to be negatively associated with HbA1C levels [49], and its expression in glomeruli was associated with diabetic nephropathy [50]. Our study found significantly higher concentrations of PAPP-A in ACS patients with T2DM than those without (19 vs. 13 ng/ml, p < 0.001).…”

The role of PAPP-A in the IGF system: location, location, location

“…Diabetic nephropathy is another pathological condition that may develop as a consequence of increased PAPP-A activity. In humans, diabetic nephropathy is associated with an elevated level of glomerular PAPP-A expression, and the absence of PAPP-A in mice confers resistance to the development of pathological hallmarks of diabetic nephropathy (Mader et al 2013).…”

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

“…We have previously reported that PAPP-A knock-out mice show decreased incidence and severity of age-related nephropathy (13). Also, 14-month-old female PAPP-A knock-out mice were resistant to experimentally-induced type 2 diabetic nephropathy (8). We had chosen female mice to do the latter studies, since the preliminary data coming out of this study indicated higher levels of PAPP-A expression in females compared to males, and, thus, we reasoned that there might be a greater effect of PAPP-A gene deletion in female mice.…”

“…These studies suggest not only diagnostic and prognostic value, but also potential therapeutic value for PAPP-A. Indeed, in the mouse, global deletion of PAPP-A has been shown to have beneficial effects promoting resistance to atherosclerotic plaque progression, visceral fat accumulation and diabetic nephropathy (8,10,11), and in the maintenance of immune competence with age (12). Furthermore, these PAPP-A knock-out mice live significantly longer than wild-type littermates (13).…”

“…In humans, elevated PAPP-A expression has been shown to be associated with acute coronary syndromes and kidney disease (2–8). It was also noted that PAPP-A was highly expressed in human preadipocytes obtained from visceral fat depots compared to those from subcutaneous fat depots (9).…”