Podocyte-targeted Heme Oxygenase (HO)-1 overexpression exacerbates age-related pathology in the rat kidney

Abstract

Although Heme Oxygenase-1 (HO-1) induction in various forms of kidney injury is protective, its role in age-related renal pathology is unknown. In the ageing kidney there is nephron loss and lesions of focal glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriolosclerosis. Underlying mechanisms include podocyte (visceral glomerular epithelial cell/GEC) injury. To assess whether HO-1 can attenuate ageing-related lesions, rats with GEC-targeted HO-1 overexpression (GEC HO-1 rats) were generated using a Sleeping Beauty (SB) transposon system and extent of lesions over a 12-month period were assessed and compared to those in age-matched wild-type (WT) controls. GEC HO-1 rats older than 6 months developed albuminuria that was detectable at 6 months and became significantly higher compared to age-matched WT controls at 12 months. In GEC HO-1 rats, lesions of focal segmental and global glomerulosclerosis as well as tubulointerstitial lesions were prominent while podocytes were edematous with areas of foot process effacement and glomerular basement membrane thickening and wrinkling. GEC HO-1 rats also developed hemoglobinuria and hemosiderinuria associated with marked tubular hemosiderin deposition and HO-1 induction, while there was depletion of splenic iron stores. Kidney injury was of sufficient magnitude to increase serum lactate dehydrogenase (LDH) and was oxidative in nature as shown by increased expression of 8-hydroxydeoxyguanosine (8-OHdg, a byproduct of oxidative DNA damage) in podocytes and tubular epithelial cells. These observations highlight a detrimental effect of podocyte-targeted HO-1 overexpression on ageing-related renal pathology and point to increased renal iron deposition as a putative underlying mechanism.

Treadmill Exercise Training Ameliorates Functional and Structural Age-Associated Kidney Changes in Male Albino Rats

“…Hence, studying the modulation of these mechanisms reflected the beneficial role of treadmill exercise on the aged kidney. The present study revealed that podocyte injury, indicated by upregulation of desmin, and downregulation of VEGF, autophagy, and AQP3 were implicated in aging-induced renal changes, which was in line with Poulaki et al [ 60 ] and Durvasula and Shankland [ 61 ], who attributed the different aging-related renal changes to podocyte injury.…”

Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression

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Regulation of Complement Activation by Heme Oxygenase-1 (HO-1) in Kidney Injury

“…It was proposed that this could serve as a mechanism to protect against detrimental effects known to occur when HO-1 is overexpressed [ 95 ]. Credence to this proposal was provided by in vivo studies demonstrating that long-term podocyte-targeted HO-1 induction in the aging rat causes podocyte injury and exacerbates age-related renal pathology [ 96 ].…”