Paracrine and endocrine regulation of renal K⁺ secretion

The seminal studies conducted by Giebisch and coworkers in the 1960s paved the way for understanding the renal mechanisms involved in K⁺ homeostasis. It was demonstrated that differential handling of K⁺ in the distal segments of the nephron is crucial for proper K⁺ balance. Although aldosterone had been classically ascribed as the major ion transport regulator in the distal nephron, thereby contributing to K⁺ homeostasis, it became clear that aldosterone per se could not explain the ability of the kidney to modulate kaliuresis in both acute and chronic settings. The existence of alternative kaliuretic and antikaliuretic mechanisms was suggested by physiological studies in the 1980s but only gained form and shape with the advent of molecular biology. It is now established that the kidneys recruit several endocrine and paracrine mechanisms for adequate kaliuretic response. These mechanisms include the direct effects of peritubular K⁺, a gut-kidney regulatory axis sensing dietary K⁺ levels, the kidney secretion of kallikrein during postprandial periods, the upregulation of angiotensin II receptors in the distal nephron during chronic changes in K⁺ diet, and the local increase of prostaglandins by low-K⁺ diet. This review discusses recent advances in the understanding of endocrine and paracrine mechanisms underlying the modulation of K⁺ secretion and how these mechanisms impact kaliuresis and K⁺ balance. We also highlight important unknowns about the regulation of renal K⁺ excretion under physiological circumstances.