SUN-133 G-protein Pathway Suppressor 2 (GPS2) Enhanced the Large Conductance Ca2+ Activated Potassium (BK) Channels Activity through modulating WNK4 Ubiquitination

Abstract

number and podocyte number play pivotal roles in the development of CKD we utilised a mouse model of low birth weight and low nephron number to investigate podocyte number in the early postnatal period and whether podocyte number is associated with increased risk of renal pathophysiology in adulthood. Methods: C57Bl6 female mice were exposed to a maternal low (LPD; 8%) or normal (NPD; 20%) protein diet for 3 weeks prior to pregnancy, throughout pregnancy and up until weaning (PN21), when the kidneys of one male and one female per litter were collected for analysis of nephron number, podocyte endowment, glomerular volume and podocyte density. A 'second-hit' was induced in remaining littermates at 6 weeks of age by administration of streptozotocin (STZ, 55mg/kg 5x daily doses; sodium citrate for control) to induce moderate to severe diabetes. These offspring were followed for a further 18 weeks with hyperglycaemia and urinary albumin/creatinine ratio measured every 2 weeks during this period. Mice were then sacrificed for podometric and histopathology analysis. Results: LPD offspring had significantly lower birth weights than NPD offspring (18% in males, p<0.01; 15% in females, p<0.01). Glomeruli in male LPD offspring were 23% smaller (p<0.0001) and had 15% fewer podocytes per glomerulus than male NPD offspring (62AE1.4 vs 72AE2.1 podocytes/glomerulus, p<0.001). In contrast, glomeruli in female LPD offspring were only 13% smaller (p<0.01) than female NPD offspring, with 9% fewer podocytes per glomerulus (61AE1.4 vs 67AE1.6, p<0.02). Male LPD diabetic offspring administered STZ had earlier onset of elevated urinary albumin excretion than male NPD diabetic offspring. Female LPD diabetic offspring had similar onset of elevated urinary albumin excretion to that of female NPD diabetic offspring. However, there was a trend for albumin excretion in female LPD diabetic mice to peak higher than that of female NPD diabetic mice (p=0.06). Conclusions: These findings demonstrate that low birth weight influences podocyte number in both male and female mice after the completion of nephrogenesis. Analysis of podocyte number and renal pathology in 24-week old offspring is continuing.