Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

Abstract

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P Ͻ 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.

The Role of the Mammalian Target Of Rapamycin (mTOR) in Renal Disease

“…76,80,83 In a rat model of progressive membranous nephropathy (Heymann nephritis), inhibition of mTOR with rapamycin ameliorated glomerular hypertrophy, decreased the renal expression of proinflammatory and profibrotic cytokines, and retarded the development of tubulointerstitial inflammation and fibrosis. 84 Similar findings were reported in animal models of CKD from other causes, including reduced renal mass from five-sixths nephrectomy, 82 renal obstruction after ureteral ligation, 81,85 and chronic mesangioproliferative glomerulonephritis induced by antiThy1 antibody. 73,86 In summary, mTOR plays an important role in the progression of CKD in a variety of animal models.…”

“…76 -80 A role for mTOR in EMT is suggested by studies showing that rapamycin inhibits EMT in some animal models of studies of DN and other forms of CKD. 72,81,82 Role of mTOR in Nondiabetic Forms of CKD Rapamycin also slows the progression of renal fibrosis and delays the onset of renal failure in experimental models of CKD due to causes other than diabetes. Many of the same events that promote progression of diabetic CKD are also important in nondiabetic forms of CKD.…”

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

“…The beneficial effects of mTOR inhibition have recently been reported in several rat models of chronic kidney disease, i.e., hypertensive 5 ⁄6 nephrectomy, diabetic nephropathy, hypertrophy following unilateral nephrectomy, tubulointerstitial fibrosis due to urethral obstruction or nephrotic syndrome, and polycystic kidney disease (2,5,10,19,26,29). These beneficial results are now expanded toward a progressive model of human mesangioproliferative nephropathy as a leading cause of end-stage kidney disease worldwide (13,14).…”

“…This may have contributed to the renoprotection observed with rapamycin treatment. With regard to their primary mode of pharmacological action (10,30), mTOR inhibitors pose no direct effect on blood pressure. Therefore, it is likely that the lower blood pressure with rapamycin in this study was mediated indirectly through less renal damage and fibrosis.…”

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

“…24-28 mTOR activity is low or absent in the normal kidney but increases markedly after AKI, 29 diabetic nephropathy, and other forms of progressive CKD. [30][31][32][33][34] We examined the activation of mTOR and evaluated whether inhibition of the mTOR pathway with rapamycin could protect against Kim-1-mediated kidney injury. As shown in Figure 7C, phosphorylated ribosomal S6 kinase (pS6K), the downstream target of mTOR, was increased in Kim-1 constitutive transgenic zebrafish at 3 months of age.…”