The INK4a proteins p16(INK4a) and p19(ARF) regulate cell cycle arrest and senescence. However, the role of these proteins in controlling these processes in the normal kidney and following injury is unknown. We performed unilateral ureteral obstruction (UUO) to induce fibrosis in 2- to 3-mo-old wild-type (WT) C57/B6 and INK4a knockout mice. By quantitative RT-PCR, p16(INK4a) levels were increased sixfold in WT mice 7 days after UUO and p19(ARF) remained undetectable. Kidney sections were examined to determine levels and localization of p16(INK4a), apoptosis, fibrosis, and senescent cells. INK4a knockout mice displayed mesangial cell proliferation, increased matrix deposition, and myofibroblast differentiation under normal conditions. Following UUO, INK4a knockout mice displayed 10-fold increased tubular and interstitial cell proliferation, 75% decreased collecting duct apoptosis, 2-fold greater collagen and fibronectin deposition, and no cell senescence by senescence-associated β-galactosidase staining compared with WT mice. Both INK4a knockout mesangial cells and kidney lysates from knockout mice following injury showed elevated levels of IL-6 by ELISA compared with WT samples. INK4a knockout epithelial cell cultures displayed increased mesenchymal cell markers when exposed to transforming growth factor-β. These results confirm that p16(INK4a) controls cell proliferation and matrix production and mitigates fibrosis following injury and suggest that the mechanism involves a role in limiting inflammation and cell proliferation.

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Acute oxalate nephropathy (AON) induced by high dietary intake of oxalate-rich food is a rare cause of acute kidney injury and end-stage renal disease (ESRD). We describe a 68-year-old man with adequate baseline renal function who developed severe AON and ESRD. Six months earlier, he started a daily oxalate-rich fruit and vegetable juice diet high in spinach, with a calculated daily oxalate dietary intake of 1500 mg, about 10 times a typical diet. Renal biopsy showed extensive tubular oxalate deposits and acute tubular damage; the renal tissue was relatively free of chronic changes such as glomerulosclerosis, tubular atrophy, and interstitial fibrosis. A year later, he remains dialysis dependent.

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