Abstract 041: Adipocyte (Pro)Renin Receptor Via SPRR Regulates Renal Sodium-glucose Cotransporter-2 Expression And Glomerular Filtration Rate In Mice

Abstract

Evidence is available to suggest a potential role of adipocyte-derived factors to control renal function but the nature of these endocrine factors largely remains elusive. Sodium-glucose cotransporter 2 (SGLT2) controls Na + delivery to the macula densa thereby determining tubuloglomerular feedback and thus glomerular filtration rate (GFR), providing the molecular basis for attenuation of glomerular hyperfiltration and diabetic kidney disease by SGLT2 inhibitors. Furthermore, we previously reported that soluble (pro)renin receptor (sPRR) inhibits obesity-induced renal SGLT2 expression, thus reducing GFR and albuminuria in a mouse model of diet-induced obesity. In the present study, we examined adipocytes as a potential source of sPRR that acts in an endocrine manner to regulate renal function, particularly GFR, through regulation of renal SGLT2 expression. PRR floxed mice was crossed with Adipoq-CreERT2 mice and gene inactivation was induced by tamoxifen in adulthood (termed as Adipo PRR KO). Under basal condition, male 4-month old Adipo PRR KO mice exhibited a 33.65% increase in GFR as assessed by transdermal measurement of GFR as compared with floxed controls (1318.26± 38.35 in KO group vs . 986.33± 14.31 ul/min/100g b.w. in floxed group, n = 6, p < 0.01). Dapagliflozin-sensitive SGLT2 activity as assessed by 6-h urinary glucose excretion was increased by 1.93 folds in Adipo PRR KO mice (SGLT2 activity: 13.19± 1.64 in KO group vs. 6.83± 1.20 mg/6h in floxed group, n=7-10, p < 0.05). Immunoblotting analysis detected a more than 10-fold increase in renal protein abundance of SGLT2 in the null mice (12.38± 1.51 in KO group vs.1.00± 0.26 in floxed group, n=6, p < 0.01) whereas the increase in renal SGLT2 mRNA was quite modest (1.25± 0.08 in KO group vs . 1.00± 0.06 in floxed group; n = 6, p < 0.05). As compared with floxed mice, Adipo PRR KO mice showed a 44.62% fall in plasma sPRR concentration as assessed by ELISA (1.18± 0.09 in KO group vs . 2.12± 0.10 ng/ml in floxed group, n = 6, p < 0.01). Taken together, the present study, for the first time, provides evidence for an endocrine action of adipocyte PRR to regulate renal SGLT2 expression and GFR likely through sPRR.