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The end of the Renaissance is as imprecisely marked as its starting point.

For many, the rise to power in Florence of the austere monk Girolamo Savonarola in 1494-1498 marks the end of the city's flourishing; for others, the triumphant return of the Medici marks the beginning of the late phase in the arts called Mannerism. Other accounts trace the end of the Italian Renaissance to the French invasions of the early 16th century and the subsequent conflict between France and Spanish rulers for control of Italian territory.[20] Savonarola rode to power on a widespread backlash over the secularism and indulgence of the Renaissance [21] his brief rule saw many works of art destroyed in the "Bonfire of the Vanities" in the centre of Florence. With the Medici returned to power, now as Grand Dukes of Tuscany, the counter movement in the church continued. In 1542 the Sacred Congregation of the Inquisition was formed and a few years later the Index Librorum Prohibitorum banned a wide array of Renaissance works of literature, which marks the end of the illuminated manuscript together with Giulio Clovio, who is considered the greatest illuminator of the Italian High Renaissance, and arguably the last very notable artist in the long tradition of the illuminated manuscript, before some modern revivals. Equally important was the end of stability with a series of foreign invasions of Italy known as the Italian Wars that would continue for several decades. These began with the 1494 invasion by France that wreaked widespread devastation on Northern Italy and ended the independence of many of the city-states. Most damaging was the May 6, 1527, Spanish and German troops' sacking Rome that for two decades all but ended the role of the Papacy as the largest patron of Renaissance art and architecture.[12] While the Italian Renaissance was fading, the Northern Renaissance adopted many of its ideals and transformed its styles. A number of Italy's greatest artists chose to emigrate. The most notable example was Leonardo da Vinci who left for France in 1516, but teams of lesser artists invited to transform the Chteau de Fontainebleau created the school of Fontainebleau that infused the style of the Italian Renaissance in France. From Fontainebleau, the new styles, transformed by Mannerism, brought the Renaissance to Antwerp and thence throughout Northern Europe. This spread north was also representative of a larger trend. No longer was the Mediterranean Europe's most important trade route. In 1498, Vasco da Gama reached India, and from that date the primary route of goods from the Orient was through the Atlantic ports of Lisbon, Seville, Nantes, Bristol, and London. These areas quickly surpassed Italy in wealth and power.