IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury.

Samiksha Wasnik,Amir Abdipour,Jintao Zhang,Brian Sutjiadi,Hongzheng Bi,David J Baylink,Justin Lyu,Xiaolei Tang,Edmundo E Carreon,Sean Wilson

doi:10.3390/ijms21114095

Abstract

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.

Highlights

Acute kidney injury (AKI) is a common disease in hospitalized elderly patients and has high morbidity and mortality
(1) We sought to evaluate whether acute kidney injury (AKI) inflammation would be associated with a decrease in serum IGF-1, as we had seen before with sepsis [12]
We found a marked decrease in serum IGF-1, and the step was to rescue this deficiency, which we did by injecting skeletal muscle with an in vivo gene therapy approach, utilizing a Lentiviral vector engineered to express IGF-1 in skeletal muscle

Summary

Introduction

Acute kidney injury (AKI) is a common disease in hospitalized elderly patients and has high morbidity and mortality. The stage of AKI that is detrimental to the patient is characterized by an increase in proinflammatory cytokines [7,8,9]. To treat this stage of AKI, we elected to utilize two therapeutic agents (IGF-1 and BTP-2). The mechanism for the decrease in serum IGF-1 in sepsis includes a depression of growth hormone receptor expression in the liver, which is a consequence of increased circulating inflammatory cytokines [12]. SOCE in turn would decrease the high cytosolic calcium typical of inflammatory conditions, including LPS administration [15,16,17,18]

Objectives

Methods

Results