Absence of the Na‐Glucose Cotransporter SGLT1 Ameliorates Kidney Recovery in a Murine Model of Acute Kidney Injury
Authors: Nespoux Josselin , Patel Rohit , Huang Winnie , Koepsell Hermann , Freeman Brent , Vallon Volker 
Published: June 2021

The renal Na‐glucose cotransporter SGLT1 reabsorbs ~3% of the filtered glucose in the late proximal tubule, a hypoxia‐sensitive tubular segment that enters the outer medulla. Pharmacological blockade of SGLT2, which in the early proximal tubule reabsorbs most of the filtered glucose, was found protective in a mouse model of acute kidney injury (AKI) induced by ischemia‐reperfusion (IR). Since little is known about the role of SGLT1 in this context, we determined whether lack of SGLT1 affects kidney injury or recovery following IR.SGLT1‐knockout (KO) and WT mice (C57BL/6J males) underwent IR or sham surgery. IR was induced by 20 minutes of bilateral renal artery clamping, while body temperature was maintained at 36–37□. Sham operation was similar to IR surgery without artery clamping. All groups (WT Sham, WT IR, SGLT1‐KO Sham and SGLT1‐KO IR, n=7–8/group) were fed a low‐glucose high‐protein diet to prevent diarrhea in SGLT1‐KO. Urine and blood were collected at several time points during recovery. GFR was measured 14 days after IR by plasma elimination kinetics of FITC‐sinistrin in conscious mice. Kidneys were harvested on day 16.On day 1 after IR, plasma creatinine (by LC‐MS‐MS) increased to similar levels in SGLT1‐KO and WT (0.554±0.08 vs. 0.470±0.1 mg/dL, p=0.351), indicating similar initial kidney impairment. In accordance, IR reduced urine osmolality and increased plasma osmolality to similar levels in SGLT1‐KO and WT on day 1, possibly as a consequence of impaired urine concentration or renal retention of waste products. This was associated with a greater increase in fractional glucose excretion in SGLT1‐KO (1 to 19%) vs WT (0.1 to 7%) (p=0.003) indicating a prominent role of SGLT1 in glucose reabsorption at this time point. On day 14, GFR was significantly lower in WT IR vs SGLT1‐KO IR (6.56±0.6 vs. 9.13±0.8 μL/min/g BW, p<0.05), associated with higher plasma creatinine levels on harvest day (0.130±0.016 vs. 0.093±0.009 mg/dL, p<0.05). Moreover, plasma osmolality remained elevated in WT IR but was normalized in SGLT1‐KO IR on day 16 (345±11 vs. 316±4 mosm/kg, p=0.006). On day 16, plasma urea levels in sham groups were higher in SGLT1 KO vs WT (18.0±0.3 vs. 13.2±0.9 mmol/L, p=0.028), possibly reflecting a proposed role of SGLT1 in renal urea secretion, unmasked by high protein diet. Plasma urea was strongly increased in WT IR vs sham (24.6±2.2 vs. 13.2±0.9 mmol/L, p<0.001), whereas levels were preserved in SGLT1‐KO IR vs sham. RT‐qPCR analyses on whole kidney tissue revealed that Na‐2Cl‐K cotransporter NKCC2 mRNA expression was decreased in WT IR but preserved in SGLT1‐KO IR, whereas renal mRNA expression of markers of injury, fibrosis and inflammation (KIM‐1, type 1 collagen, MCP‐1) was lower in SGLT1‐KO IR vs WT IR.Lack of SGLT1 improved kidney recovery in a mouse model of IR‐induced AKI. The results may reflect a deleterious role of SGLT1 activity in the late proximal tubule for outer medullary integrity in the aftermath of IR‐induced AKI. This may impair tubular function (reduced NKCC2) with consequences on GFR, kidney integrity, and body homeostasis, and have therapeutical implications.Support or Funding InformationNIH R01DK106102, R01DK112042, P30DK079337, and the Department of Veterans AffairsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.