Congenital anomalies of the kidney and urinary tract (CAKUT), which include solitary kidney and congenital renal hypoplasia, constitute the most common cause of chronic kidney disease (CKD) in children. Hyperfiltration is central to the progression of CKD in children. There is no specific treatment for hyperfiltration-mediated injury in children with CAKUT. Currently used regimens are extrapolations of treatments designed for adult patients to minimize kidney injury from hypertension, diabetes and proteinuria. The long-term goal of our research is to develop novel agents to attenuate the effects of hyperfiltration to delay the progression of CKD in children with CAKUT. Mice with lower nephron numbers will be used to understand the mechanism of, and to develop strategies for attenuating the hyperfiltration- mediated glomerular injury. Podocytes regulate plasma ultrafiltration from the glomerular capillary into Bowman's space. Increased ultrafiltrate along podocyte cell body causes fluid flow shear stress (FFSS) and capillary stretch causes tensile stress on podocyte foot processes. The shearing effect of FFSS on podocytes is not well understood. Unilateral nephrectomy (UNX) causes a 1.5-2 fold increase in FFSS in rodent models. FFSS increases COX-2 expression and prostaglandin E2 (PGE2) synthesis in podocytes, and glomerular albumin permeability. Of the four PGE2 receptors, FFSS upregulates only EP2, which in turn activates ?-catenin. Our hypothesis is that EP2 receptor blockade will attenuate the hyperfiltration-mediated injury. Proposed research under Aim 1 will determine the role of EP2 in FFSS-mediated glomerular injury using EP2 specific antagonist (PF-4418948) and agonist (ONO-AE1-259) in models of solitary kidney (UNX sv129 mice), congenital renal hypoplasia (ROP Os/+ mice), and EP2 null mice.
Aim 2 will address the significance of EP2-mediated ?-catenin activation using mice with constitutively active ?-catenin in podocytes, TOPGAL mice with ?-galactosidase as a measure of in vivo ?-catenin activation, and the mice from Aim 1. Roles of EP2 and EP4 in FFSS and tensile stress will be distinguished using EP2 and EP4 antagonists and agonists. Results from Aim 3 will highlight temporal changes in urinary eicosanoids in children with solitary kidney and CAKUT. These data will validate findings from Aim 1 and form the basis for translational work. Overall, confirming EP2 as the principal receptor will lead to repurposing and development of specific agents to treat hyperfiltration-mediated glomerular injury in children with CAKUT.
In children born with single or abnormal kidneys (children with CAKUT), the kidney initially adapts to additional workload by increasing filtration (hyperfiltratio), which over time leads to progression of chronic kidney disease (CKD). We propose to identify molecular targets to specifically treat CKD in children with CAKUT. Animal and cellular models will be used to understand the mechanism of injury from hyperfiltration, to identify novel molecular targets, and to test repurposed and new drugs to slow down kidney disease in children with CAKUT.
|Srivastava, Tarak; Hariharan, Sundaram; Alon, Uri S et al. (2018) Hyperfiltration-mediated Injury in the Remaining Kidney of a Transplant Donor. Transplantation 102:1624-1635|
|Srivastava, Tarak; Dai, Hongying; Heruth, Daniel P et al. (2018) Mechanotransduction signaling in podocytes from fluid flow shear stress. Am J Physiol Renal Physiol 314:F22-F34|
|Sharma, Mukut; Sharma, Ram; McCarthy, Ellen T et al. (2017) Hyperfiltration-associated biomechanical forces in glomerular injury and response: Potential role for eicosanoids. Prostaglandins Other Lipid Mediat 132:59-68|
|Srivastava, Tarak; Thiagarajan, Ganesh; Alon, Uri S et al. (2017) Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract. Nephrol Dial Transplant 32:759-765|