principal cell

**Location:** Late distal convoluted tubule, connecting tubule, and cortical/medullary collecting duct. Intercalated cells (alpha and beta) are interspersed among them and handle acid-base balance.

**Functions and mechanisms:** - **Na+ reabsorption:** Na+ enters through apical epithelial sodium channels (ENaC). The basolateral Na+/K+-ATPase maintains the low intracellular Na+ gradient. This creates a lumen-negative potential. - **K+ secretion:** K+ moves from the cell into the lumen through apical ROMK (and BK) channels. The lumen-negative potential favors this. - **Aldosterone:** It binds an intracellular mineralocorticoid receptor. This increases ENaC and ROMK expression and Na+/K+-ATPase activity. The result is more Na+ reabsorption and more K+ secretion (and H+ secretion by adjacent alpha-intercalated cells). Excess aldosterone causes hypokalemia and metabolic alkalosis. Deficiency causes hyperkalemia and metabolic acidosis. - **ADH (vasopressin):** It binds V2 receptors on the basolateral membrane (Gs → cAMP → PKA). This causes insertion of aquaporin-2 (AQP2) into the apical membrane. Water leaves the lumen through AQP2 and exits through basolateral AQP3 and AQP4. Urine becomes concentrated.

**Clinical correlations:** - **Spironolactone/eplerenone:** They are competitive aldosterone receptor antagonists. They cause hyperkalemia and gynecomastia (spironolactone). - **Amiloride/triamterene:** They block ENaC directly. They cause hyperkalemia and metabolic acidosis. Amiloride is also used in lithium-induced nephrogenic diabetes insipidus (lithium enters principal cells via ENaC). - **Loop and thiazide diuretics:** They increase Na+ delivery to principal cells. This raises K+ secretion and causes hypokalemia. - **Liddle syndrome:** There is a gain-of-function mutation in ENaC (β or γ subunit). It causes hypertension, hypokalemia, and metabolic alkalosis with low renin and low aldosterone. Treat with amiloride, not spironolactone. - **Pseudohypoaldosteronism type 1:** It is caused by loss-of-function ENaC mutations. It causes salt wasting, hypotension, and hyperkalemia with high renin and high aldosterone. - **Nephrogenic DI:** The V2 receptor or AQP2 is defective, or the cells are resistant to ADH (lithium, demeclocycline, hypercalcemia). Principal cells fail to concentrate urine, so it is dilute and polyuric. It does not respond to desmopressin. Central DI does respond. - **SIADH:** ADH excess increases AQP2 insertion, causing euvolemic hyponatremia with concentrated urine. Tolvaptan and conivaptan are V2 antagonists. Demeclocycline is also used. - **Apparent mineralocorticoid excess / licorice ingestion:** 11β-HSD2 is deficient or inhibited. Cortisol then activates the mineralocorticoid receptor in principal cells. This causes hypertension and hypokalemia with low aldosterone.

**High-yield contrast:** Principal cells handle Na+/K+/H2O (aldosterone and ADH). Intercalated cells handle acid-base: alpha cells secrete H+ via H+-ATPase and H+/K+-ATPase, and beta cells secrete HCO3-.