Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). However, the mechanisms that regulate renal function in response to SGLT2i have not been fully elucidated. We explored the renal protective mechanisms of SGLT2i with empagliflozin (EMPA), with a focus on glomerular hemodynamic effects and TGF using in vivo multiphoton microscope (MPM) imaging techniques. C57BL/6 mice and spontaneously diabetic Ins2 Akita (AKITA) mice were used. The mice were treated with EMPA (20mg/kg/day) and insulin for four weeks, and single-nephron GFR (SNGFR) was measured using MPM. An nNOS inhibitor (7-nitroindazole, 20mg/kg/day) or a COX2 inhibitor (SC58236, 6mg/L), or an adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg/day) were administered to elucidate mechanisms of TGF signaling and SNGFR regulation. The urinary excretion of adenosine, nitric oxide metabolites (NOx) and the prostanoid PGE2 was also quantified. SNGFR in the AKITA group was higher compared to controls (C57BL/6; 4.9±1.3 nl/min vs. AKITA; 15.8±6.8 nl/min) and decreased in AKITA/EMPA to 8.0±3.3 nl/min (p<0.01). In vivo imaging also revealed concomitant afferent arteriolar dilation (p<0.01) and increased glomerular permeability of albumin in the AKITA group. EMPA ameliorated these changes (p<0.01). Urinary adenosine excretion in the AKITA/EMPA group was higher compared to AKITA (AKITA; 3.4±1.4 nmol/day, AKITA/EMPA; 11.2±3.0 nmol/day, p<0.05), while NOx and PGE2 did not differ. A1aR antagonism, but not nNOS or COX2 inhibition, blocked the effect of EMPA on renal function. EMPA increased urinary adenosine excretion and reduced hyperfiltration via afferent arteriolar constriction, effects that were abolished by A1aR blockade. The adenosine/A1aR system plays a pivotal role in the regulation of SNGFR via TGF mechanisms in DKD.
K. Kidokoro: Research Support; Spouse/Partner; Sanwa Kagaku Kenkyusho Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Inc., MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Takeda Pharmaceutical Co., Astellas Pharma Inc., TORII PHARMACEUTICAL Co.. Y. Sogawa: None. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. V. Kulasingam: None. H. Nagasu: None. M. Satoh: None. T. Sasaki: None. N. Kashihara: None.