Abstract 014: B1 Integrin is Essential for Kidney Structure, Function and Vascular Development

Abstract

Integrins are the largest family of cell adhesion molecules. β1-Integrin (Itgb1) is the most abundantly expressed β subunit and is present in almost every cell type. Previous studies showed that Itgb1 is required for normal development of the ureteric bud and podocytes and for the function of the proximal tubule. However, its role in the kidney vasculature has not been explored. Renin cells are crucial for blood pressure homeostasis and for normal nephrovascular development. The mechanisms involved in their morphogenetic functions are not well understood. We found that Itgb1 is highly expressed in renin expressing cells throughout development. Therefore, to study the role of Itgb1 in renin cells we generated a conditional deletion (cKO) of Itgb1 in cells of the renin lineage by crossing floxed Itgb1 mice with mice expressing cre recombinase driven by the renin locus. Itgb1 cKO mice were smaller in size (20.32 ± 4.35 g vs 29.55 ± 7.39 g, p=0.016 ), had smaller kidney to body weight ratio (0.92 ± 0.30 vs 1.31 ± 0.30, p=0.017 ), hypotension (MABP 82.33 ± 4.00 mmHg vs 92.55 ± 7.72 mmHg, p=0.02 ), anemia (hemoglobin 11.26 ± 1.48 g/dL vs 15.07 ± 1.31 d/dL, p=0.003 ; hematocrit 40.39 ± 5.48% vs 53.8 ± 4.21%, p=0.002 ), renal failure (BUN 71.44 ± 32.81 mg/dL vs 29.4 ± 7.67mg/dL, p=0.004), and lower plasma renin levels (6664.58 ± 3251.92 vs 43357.09 ± 17032.63 pg/ml, p =0.001 ). Mutants also developed hyposthenuria (urine osmolality 452 ± 138.98 mOsm/kg vs 1460.5 ± 482.09 mOsm/kg, p<0.02 ). Histological analysis revealed excessive collagen deposition in the interstitium and peri-glomerular areas; fibrocystic glomeruli; tubular dilatation and protein casts in the tubules. Immunostaining for renin and α-smooth muscle actin showed a marked decrease in renin protein expression and abundant α-smooth muscle actin expression in the interstitium. Microdissection of the renal arterial tree combined with renin immunostaining confirmed the marked decrease in renin and evidenced the overall vascular abnormalities including fewer and shorter arterial and arteriolar branches. Overall, this study shows that β1-Integrin in cells of the renin lineage is crucial for renin expression, morphogenesis of the renal vasculature and maintenance of the normal kidney architecture and function.