Abstract: SA-PO568
Integrin β6 Knockout Ameliorates Glomerular Sensitization to Podocyte-Specific Injury
Session Information
- Glomerular Diseases: Fibrosis, Extracellular Matrix
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Wang, Jiayi, Vanderbilt University Medical Center, Nashville, United States
- Li, Xin, The Medicine College of Shanghai JiaoTong University, Shanghai, China
- Matsusaka, Taiji, Tokai University School of Medicine, Isehara, Kanagawa, Japan
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
We previously showed that even mild tubulointerstitial injury sensitized glomeruli to subsequent podocyte-specific injury. We also showed that tubulointerstitial fibrosis was decreased in integrin β6-/- mice. Integrin avβ6 is expressed on some tubular epithelial cells, including macula densa, but not on glomerular tufts, and activates latent TGFβ. We aimed to investigate whether β6-/- mice had ameliorated sensitization to glomerular injury induced by initial tubular injury, and possible mechanisms of β6 in tubuloglomerular crosstalk.
Methods
Wild type (WT) or β6-/- mice were mated with NEP25 mice which express human CD25 on podocytes that can be injured with specific toxin (LMB2) injection. A sequential tubular-glomerular injury model was performed by inducing acute tubular injury by aristolochic acid injection at wk 0, followed by podocyte injury by LMB2 injection at wk 8, when tubular injury had functionally recovered. Uninephrectomy was performed at wk 9 and mice sacrificed at wk 12. Effects of β6 on tubuloglomerular feedback were assessed by adding high salt from wk 6 in subgroups.
Results
KIM-1 expression in tubules was decreased in β6-/- at wk 8 after tubular injury but with only numerically reduced interstitial fibrosis (Sirius red morphometry). However, even this minor tubulointerstitial protection by β6 deficiency resulted in a marked effect on glomerular sensitization to podocyte injury. β6-/- mice had less albuminuria and glomerulosclerosis with more preserved GFR and WT1+ cells vs WT, with less TGFβ activation. Further, WT subgroups treated with high salt had greater increase in urinary sodium excretion, compared to normal salt, vs β6-/-. High salt increased calculated single-nephron GFR (SNGFR) in β6-/- but not in WT, with less decrease in renin RNA and protein in β6-/-. NKCC2 activity (measured by OXSR1 and VAMP2 expression), adenosine formation enzyme (ecto-5–nucleotidase) and A1 adenosine receptor were lower in high salt exposed β6-/- vs WT.
Conclusion
We conclude that integrin β6-/- show very mild amelioration of acute tubular injury and interstitial fibrosis vs WT, but still show markedly less glomerular sensitization to subsequent podocyte-specific injury, which is contributed to by blunted tubuloglomerular feedback. We postulate that β6 may, in addition to effects on tubulointerstitial injury, also modulate macula densa function.
Funding
- NIDDK Support