Renal Tubule-Specific NRF2 Deletion Downregulates SGLT2 and Angiotensinogen Expression and Ameliorates GFR and Kidney Injury in Akita Mice
Bibliographic record
Abstract
Background: Nuclear factor erthyroid-2 related factor 2 (NRF2) expression is increased in kidneys of mice and patients with diabetes. We have reported that overexpression of NRF2 in renal proximal tubular cells (RPTCs) increases sodiumglucose co-transporter 2 (SGLT2) and angiotensinogen (AGT) expression and exacerbates dysglycemia and progression of nephropathy in type 1 diabetic (T1D) Akita Nrf2-/-/Nrf2RPTC transgenic (Tg) mice (Diabetes 2021). However, the pathophysiological role of renal NRF2 in the progression of diabetic kidney disease (DKD) is not well understood. We now report the impact of Nrf2 deletion specifically in renal tubules (RT) of Akita mice on the expression of SGLT2 and AGT in RPTCs in the setting of hyperglycemia and kidney injury. Methods: Akita RT-specific Nrf2 knock-out (Akita Nrf2RT KO) mice were generated by crossbreeding Akita with Nrf2RT KO mice using Pax8-Cre (through crossbreeding male Nrf2 floxed mice with female RT-specific Cre deleter (Pax8-Cre) mice). Immunostaining on kidney sections, Western blot (WB) and real-time qPCR (RT-qPCR) were employed to assess protein and gene expression in isolated RPTs. Physiological and kidney morphological changes were assessed in male Akita Nrf2RT KO, Akita Nrf2lox/lox, non-diabetic Nrf2lox/lox and Nrf2RT KO mice at the age of 10 to 20 weeks. Results: SGLT2 and AGT expression in RPT were significantly lower in Akita Nrf2RT KO mice cf. to Akita mice. Glomerular filtration rate (GFR) was increased in Akita mice but was normalized (reversed glomerular hyperfiltration) in Akita Nrf2RT KO mice. Fasting blood glucose, glomerular tuft volume, RPTC volume, tubular luminal dilatation, tubular injury score, kidney weight and urinary albumin-creatinine ratio (ACR) were significantly increased in Akita mice vs nondiabetic Nrf2lox/lox and Nrf2RT KO mice. These abnormalities were greatly reduced in Akita Nrf2RT KO mice, except for fasting blood glucose. Fractional excretion of glucose was increased in Akita mice and increased further in Akita Nrf2RT KO mice. Conclusions: Our results show that RT-Nrf2 deletion ameliorates GFR and kidney injury in Akita mice, indicating renal NRF2 is important in tubuloglomerular feedback via down-regulation of intrarenal SGLT2 and AGT expression. Funding: Government Support - Non-U.S.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".