Abstract
Hypertension is a risk factor for renal impairment. While treatment of hypertension provides significant renal protection, there is still an unmet need requiring further exploration of additional pathogenetic mechanisms. We have found that the hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is involved in renal repair. HCaRG is a small intracellular protein of 225 amino acids and its gene expression is negatively regulated by extracellular calcium concentrations. HCaRG is mostly expressed in the kidneys, with higher levels found in the spontaneously hypertensive rat than in normotensive rats. In an acute kidney injury model, HCaRG expression decreases immediately after injury but increases above baseline during the repair phase. In cell cultures, HCaRG has been shown to facilitate differentiation and to inhibit cell proliferation via p21 transactivation through the p53-independent signaling pathway. Induction of p21 independently of p53 is also observed in transgenic mice overexpressing HCaRG during the repair phase after ischemia/reperfusion injury, resulting in their improved renal function and survival with rapid re-differentiation of proximal tubular epithelial cells. In addition, transgenic mice recover rapidly from the inflammatory burst most likely as a result of maintenance of the tubular epithelial barrier. Recent studies indicate that facilitating re-differentiation and cell cycle regulation in injured renal proximal tubules might be important functions of HCaRG. We have proposed that HCaRG is a component of differential genetic susceptibility to renal impairment in response to hypertension.
Highlights
High blood pressure is a risk factor for renal failure
In the obstructed kidneys after 10 days of ureteral obstruction (UUO), HCaRG overexpression decreases only the number of proliferating tubular cells, as after Ischemia/reperfusion injury (IRI) (Fig. 4b). The results in both IRI and UUO models can be summarized as follows: (1) HCaRG overexpression does not reduce initial edema, hypertrophy and injury; (2) HCaRG overexpression leads to faster kidney weight (KW) diminution in Tg than in non-Tg mice; (3) these KW decreases are due to inhibition of cell proliferation increment in tubules but not in the interstitium; (4) HCaRG elicits re-differentiation via p21 induction after injury
Acute kidney injury occurs in various clinical settings, including renal ischemia arising from septic shock and major cardiovascular surgery, or acute drug or toxic exposure
Summary
High blood pressure is a risk factor for renal failure. It is well known that malignant hypertension leads to kidney injury and that mild to moderate chronic hypertension can accelerate the progression of renal disease. Induction of p21 independently of p53 is observed in transgenic mice overexpressing HCaRG during the repair phase after ischemia/reperfusion injury, resulting in their improved renal function and survival with rapid re-differentiation of proximal tubular epithelial cells. Keywords Acute kidney injury Á Copper metabolism MURR1 domain-containing proteins Á Hypertensionrelated calcium-regulated gene Á p21 Á Re-differentiation Á Renal repair
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