Wall Tension and Tubular Resistance in Kidney Cystic Conditions

Abstract

The progressive formation of single or multiple cysts accompanies several renal diseases. Specifically, (i) genetic forms, such as adult dominant polycystic kidney disease (ADPKD), and (ii) acquired cystic kidney disease (ACKD) are probably the most frequent forms of cystic diseases. Adult dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by multiple kidney cysts and systemic alterations. The genes responsible for the condition are known, and a large amount of literature focuses on the molecular description of the mechanism. The present manuscript shows that a multiscale approach that considers supramolecular physical phenomena captures the characteristics of both ADPKD and acquired cystic kidney disease (ACKD) from the pathogenetic and therapeutical point of view, potentially suggesting future treatments. We first review the hypothesis of cystogenesis in ADPKD and then focus on ACKD, showing that they share essential pathogenetic features, which can be explained by a localized obstruction of a tubule and/or an alteration of the tubular wall tension. The consequent tubular aneurysms (cysts) follow Laplace’s law. Reviewing the public databases, we show that ADPKD genes are widely expressed in various organs, and these proteins interact with the extracellular matrix, thus potentially modifying wall tension. At the kidney and liver level, the authors suggest that altered cell polarity/secretion/proliferation produce tubular regions of high resistance to the urine/bile flow. The increased intratubular pressure upstream increases the difference between the inside (Pi) and the outside (Pe) of the tubules (∆P) and is counterbalanced by lower wall tension by a factor depending on the radius. The latter is a function of tubule length. In adult dominant polycystic kidney disease (ADPKD), a minimal reduction in the wall tension may lead to a dilatation in the tubular segments along the nephron over the years. The initial increase in the tubule radius would then facilitate the progressive expansion of the cysts. In this regard, tubular cell proliferation may be, at least partially, a consequence of the progressive cysts’ expansion. This theory is discussed in view of other diseases with reduced wall tension and with cysts and the therapeutic effects of vaptans, somatostatin, SGLT2 inhibitors, and potentially other therapeutic targets.

Modern paradigm in the diagnosis of cystic diseases of the kidneys

“…Інфікована УЗД з контрастним підсиленням може бути корисним для виявлення васкуляризації перегородок або вузлових виступів у кісті нирки та може допомогти відрізнити доброякісну кісту від невизначеної кісти або злоякісної кісти [38][39][40].…”

Decoupling shear stress and pressure effects in the biomechanics of autosomal dominant polycystic kidney disease using a perfused kidney-on-chip

“…On renal epithelial cells, flow has been reported to reinforce the apical domain of F-actin cytoskeleton 5 , as well as adherens junctions and tight junctions between cells 2 , to redistribute cytoskeletal tension and remodel focal adhesions 6 , and to trigger the expression of specific genes, in particular associated with endocytosis and reabsorption 7 . Flow is also intrinsically associated with intraluminal (transmural) pressure, which triggers cell distension 8 and activates mechanotransduction pathways that are potentially different to those triggered by shear stress. Epithelial renal cells are thus constantly submitted apically to hydrodynamic constraints, flow shear stress, and luminal pressure 9 .…”