Integrin β6 in Macula Densa Contributes to Tubuloglomerular Crosstalk

Abstract of the paper:Integrin β6 activates transforming growth factor-β on tubular cells. β6-/- mice are protected against tubulointerstitial fibrosis, but effects on glomerular injury are unclear. We studied effects of β6-/- in two kidney injury models. Non-hypertensive injury was induced in mice with a toxin receptor on podocytes (Nep25) with intact or knockout of β6 by aristolochic acid-induced tubular injury and toxin podocyte injury. β6-/-/Nep25 mice had less interstitial fibrosis and glomerulosclerosis than Nep25 mice with intact β6. However, after hypertensive 5/6 nephrectomy (Nx), β6-/- mice had milder tubulointerstitial fibrosis but more glomerulosclerosis than wild type (WT). Key tubuloglomerular feedback (TGF) modulators, nNOS, COX-2, and renin, were similar in β6-/-/Nep25 and Nep25 mice after nonhypertensive injury. After 5/6 Nx, nNOS was decreased and renin was increased in β6-/- vs WT mice. GFR response to acute volume expansion, an indicator of classic TGF, was delayed in β6-/- mice vs WT. Adding high salt to the nonhypertensive model resulted in less hypertension and sodium excretion but higher GFR in β6-/-/Nep25 vs Nep25 mice. High salt added to 5/6 Nx resulted in higher sodium excretion but lower GFR in β6-/- vs WT. In vitro, knockdown of β6 in macula densa cells increased Na+–K+–2Cl− cotransporter and high salt altered TGF molecules in WT but not in β6 deficient cells. In conclusion, deletion of integrin β6 influences tubuloglomerular crosstalk by decreasing interstitial fibrosis and blunting TGF, with paradoxical increased glomerulosclerosis in hypertensive, but not in non-hypertensive conditions.This dataset contains detailed methods and original data relevant to the paper:A Word file providing comprehensive descriptions of animal models.An Excel file comprising all biological and molecular biology original analysis data from in vivo and in vitro studies.