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Indeed, NHE3 activity is finely regulated by a variety of stimuli, both acutely and chronically, and its transport function is fundamental for a multiplicity of severe and world-wide infection-pathological conditions. This review aims to provide a concise overview of NHE3 physiology and discusses the role of NHE3 in clinical conditions of prominent importance, specifically in hypertension, diabetic nephropathy, heart failure, acute kidney injury, and diarrhea. Study of NHE3 function in models of these diseases has contributed to the deciphering of mechanisms that control the delicate ion balance disrupted in these disorders. The majority of the findings indicate that NHE3 transport function is activated before the onset of hypertension and inhibited thereafter; NHE3 transport function is also upregulated in diabetic nephropathy and heart failure, while it is reported to be downregulated in acute kidney injury and in diarrhea. 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