SPRED proteins are inhibitors of the MAPK signaling pathway. To investigate the physiological consequences of SPRED-deficiency, we generated SPRED2 knockout mice. Loss of SPRED2 caused kidney deterioration and hydronephrosis characterized by extremely dilated renal pelves and Bowman´s capsules. Extensive atrophy of cortex and medulla was accompanied by lymphocytic infiltration, disintegration of tubules and apoptosis of tubular cells. Examination of drinking behaviour revealed a nearly doubled daily water uptake (114.7 vs. 200.0 ml*gBW^-1*24h^{- 1}; p<0.001) of SPRED2^-/- mice, induced by significantly elevated serum osmolality (310.3 vs. 318.3 mosmol/kg, p<0.01) and Na⁺ (146.3 vs. 152.1 mmol/l, p<0.001) and Cl^- levels (114.4 vs. 120.7 mmol/l, p<0.001). To clarify salt and water imbalances, we systematically analyzed hormones involved in the renin-angiotensin system and the HPA axis. Whereas no significant differences could be detected for serum vasopressin (79.4 vs. 74.9 pg/ml), angiotensin II was significantly decreased (1.17 vs. 0.49 ng/ml, p<0.01), but aldosterone levels significantly elevated (365.6 vs. 600.1 pg/ml, p<0.05) in SPRED2^-/- mice, accompanied by higher or deregulated expression of aldosterone synthase in knockout adrenal glands. In line with the elevated aldosterone levels, HPA hormone secretion was significantly upregulated in knockouts, e.g. CRH (499.0 vs. 652.6 pg/mg protein, p<0.001), ACTH (0.90 vs. 1.28 ng/ml, p<0.05) and corticosterone (315.9 vs. 635.2 ng/ml, p<0.001). Immunohistochemistry and expression profiling underlined the importance of SPRED2 in tissues of the HPA axis. Western blot analysis revealed an increased ERK phosphorylation in HPA tissues of knockout mice confirming the inhibitory effect of SPREDs in vivo. We conclude that the SPRED2-deficiency leads to an upregulated MAPK signaling, causing an elevated HPA hormone secretion, which further results in salt and water imbalances and is associated with kidney deterioration.