Optical Clearing in the Kidney Reveals Potassium-Mediated Tubule Remodeling

Abstract

Summary: Distal nephron remodeling contributes to the pathophysiology of many clinically relevant scenarios, including diuretic resistance and certain Mendelian disorders of blood pressure. However, constitutive genetic disruptions are likely to have substantial developmental effects in this segment, and whether tubule remodeling upon physiological stimuli is a normal homeostatic mechanism is not known. Since the distal nephron acts as a potassium sensor, we assessed proliferation and tubule length in three dimensions upon dietary or inducible genetic manipulation by using optical clearing of adult mouse kidneys, whole-mount immunolabeling, and advanced light microscopy. We show that dietary potassium restriction leads promptly to proliferation of various nephron segments, including the distal convoluted tubule, whereas disruption of the potassium sensor Kir4.1 causes atrophy, despite ambient hypokalemia. These results provide proof that kidney tubules adapt rapidly to diet and indicate the power of clearing approaches to assess cell number and tubule length in healthy and diseased kidney. : Saritas et al. use optical clearing, immunolabeling, and advanced light microscopy to assess potassium-mediated tubule remodeling in adult mouse kidneys. A low-potassium diet induced proliferation in specific tubule segments, including the distal convoluted tubule, and deletion of the renal potassium sensor Kir4.1 led to shortening of the distal convoluted tubule. Keywords: optical kidney clearing, CLARITY, ethyl cinnamate, tubule remodeling, low-potassium diet, hypokalemia, Kir4.1, NCC, DCT, AQP2