Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract.
Congenital anomalies of the kidney and urinary tract (CAKUT) including solitary kidney constitute the main cause of progressive chronic kidney disease (CKD) in children. Children born with CAKUT develop signs of CKD only during adolescence and do not respond to renin-angiotensin-aldosterone system blockers. Early cellular changes underlying CKD progression to end-stage renal disease by early adulthood are not well understood. The mechanism of maladaptive hyperfiltration that occurs from loss of functional nephrons, including solitary kidney, is not clear. We re-examine the phenomenon of hyperfiltration in the context of biomechanical forces with special reference to glomerular podocytes. Capillary stretch exerts tensile stress on podocytes through the glomerular basement membrane. The flow of ultrafiltrate over the cell surface directly causes fluid flow shear stress (FFSS) on podocytes. FFSS on the podocyte surface increases 1.5- to 2-fold in animal models of solitary kidney and its effect on podocytes is a subject of ongoing research. Podocytes (i) are mechanosensitive to tensile and shear forces, (ii) use prostaglandin E2, angiotensin-II or nitric oxide for mechanoperception and (iii) use specific signaling pathways for mechanotransduction. We discuss (i) the nature of and differences in cellular responses to biomechanical forces, (ii) methods to study biomechanical forces and (iii) effects of biomechanical forces on podocytes and glomeruli. Future studies on FFSS will likely identify novel targets for strategies for early intervention to complement and strengthen the current regimen for treating children with CAKUT.
Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA.|Renal Research Laboratory, Research and Development, Kansas City VA Medical Center, Kansas City, MO, USA.
Tarak
T
Srivastava
School of Computing and Engineering, University of Missouri at Kansas City, MO, USA.
Ganesh
G
Thiagarajan
Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA.
Uri S
US
Alon
Renal Research Laboratory, Research and Development, Kansas City VA Medical Center, Kansas City, MO, USA.
Ram
R
Sharma
Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA.
Ashraf
A
El-Meanawy
Kidney Institute, Kansas University Medical Center, Kansas City, KS, USA.
Ellen T
ET
McCarthy
Renal Research Laboratory, Research and Development, Kansas City VA Medical Center, Kansas City, MO, USA.
Virginia J
VJ
Savin
Renal Research Laboratory, Research and Development, Kansas City VA Medical Center, Kansas City, MO, USA.
Mukut
M
Sharma
D000818:Animals; D001696:Biomechanical Phenomena; D005919:Glomerular Filtration Rate; D006801:Humans; D051436:Renal Insufficiency, Chronic / Q000151:congenital / Q000503:physiopathology*; D015398:Signal Transduction; D014570:Urologic Diseases / Q000151:congenital / Q000503:physiopathology*
CAKUT; fluid flow shear stress; hyperfiltration; podocytes; tensile stress