SPREDs are inhibitors of mitogen-activated protein kinase (MAPK) signaling. To elucidate SPRED2 in vivo function, we characterized body homeostasis in SPRED2^-/- mice. They showed a doubled daily water uptake, induced by elevated serum osmolality, originating from increased blood salt load. Doubled serum aldosterone was accompanied by augmented adrenal aldosterone synthase expression. Surprisingly, serum vasopressin was unaltered and, evidenced by halved angiotensin II levels, the renin angiotensin system was down-regulated. Adrenocorticotropic hormone (ACTH) was significantly elevated in SPRED2^-/- mice, together with its secretagogue corticotropin-releasing hormone (CRH) and its downstream target corticosterone. Extracellular signal-regulated kinase (ERK) phosphorylation in brains was augmented and hypothalamic CRH mRNA levels were elevated, both contributing to the increased CRH release. Our data were supported by CRH promoter reporter assays in hypothalamic mHypoE-44 cells, revealing a SPRED-dependent inhibition of ERK/E-twenty six (Ets)-dependent transcription. Furthermore, SPRED suppressed CRH production in these cells. In conclusion, our study suggests that SPRED2-deficiency leads to an increased MAPK signaling, which results in an augmented CRH promoter activity. The subsequent CRH overproduction causes a thereof dependent up-regulation of HPA hormone secretion. This constitutes a possible trigger for the observed compulsive grooming in SPRED2^-/- mice and may, together with hyperplasia of aldosterone-producing cells, contribute to the hyperaldosteronism and homeostatic imbalances.