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Abstract
The Goldblatt’s 2 kidney 1 clip (2K1C) rat animal model of renovascular hypertension is characterized by ischemic nephropathy of the clipped kidney. 2K1C rats were treated with a specific peroxisome proliferator-activated receptor δ (PPARδ) agonist, HPP593. Clipped kidneys from untreated rats developed tubular and glomerular necrosis and massive interstitial, periglomerular and perivascular fibrosis. HPP593 kidneys did not exhibit any histochemical features of necrosis; fibrotic lesions were present only in perivascular areas. Necrosis in the untreated clipped kidneys was associated with an increased oxidative stress, up regulation and mitochondrial translocation of the pro-death protein BNIP3 specifically in tubules. In the kidneys of HPP593-treated rats oxidative stress was attenuated and BNIP3 protein decreased notably in the mitochondrial fraction when compared to untreated animals. In untreated clipped kidneys, mitochondria were dysfunctional as revealed by perturbations in the levels of MCAD, COXIV, TFAM, and Parkin proteins and AMPK activation, while in HPP593-treated rats these proteins remained at the physiological levels. Nuclear amounts of oxidative stress-responsive proteins, NRF1 and NRF2 were below physiological levels in treated kidneys. Mitochondrial biogenesis and autophagy were inhibited similarly in both treated and untreated 2K1C kidneys as indicated by a decrease in PGC1-α and deficiency of the autophagy-essential proteins LC3-II and ATG5. However, HPP593 treatment resulted in increased accumulation of p62 protein, an autophagic substrate and an enhancer of NRF2 activity. Therefore, inhibition of BNIP3 activation by the preservation of mitochondrial function and control of oxidative stress by PPARδ is the most likely mechanism to account for the prevention of necrotic death in the kidney under conditions of persistent ischemia.
Highlights
Renal artery stenosis (RAS) is a leading cause of renovascular hypertension and ischemic nephropathy eventually developing to end-stage renal disease
Our data demonstrate that renal atrophy induced by experimental RAS can be inhibited by the pharmacological activation of peroxisome proliferator-activated receptor d (PPARd) by its agonist, HPP593 (Figure 1, 2)
Necrotic death of epithelial cells in the clipped kidneys was critically dependent on up-regulation and mitochondrial translocation of the cell death protein BNIP3 since a significant decrease of BNIP3 expression and activation resulted in complete inhibition of necrosis (Figure 1)
Summary
Renal artery stenosis (RAS) is a leading cause of renovascular hypertension and ischemic nephropathy eventually developing to end-stage renal disease. In a commonly used animal model for RAS, the Goldblatt’s 2-kidney-1-clip (2K1C), the effects of ischemia can be examined in the clipped kidney and the effects of hypertension in the collateral kidney [1]. The exact mechanisms and signaling pathways which trigger renal cell death in stenotic kidneys remain unclear. Clinical and animal studies demonstrated a critical involvement of oxidants and hypoxia in the genesis of renal atrophy [3,4]. Under conditions of oxidative stress and hypoxia, programmed cell death pathways are under control of an atypical BH3-only protein BNIP3 (Bcl and adenovirus E1B 19 kDa interacting protein 3) [5,6,7,8,9]. Mitochondria-anchored BNIP3 can contribute to mitochondria-quality control by triggering proteolytic degradation of mitochondrial proteins and clearance of damaged mitochondria by activation of autophagy [6,20,23,24,25,26,27]
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