Modulation of renal cell injury by heat shock proteins: lessons learned from the immature kidney.
ABSTRACT The mechanisms that underlie tolerance to injury in immature animals and tissues have been a subject of interest since 1670. Observations in neonatal units that premature infants are less prone to develop acute renal failure than adults in critical care units have prompted a series of investigations. Although initially attributed to metabolic adaptation such as increased glycolytic capacity and preservation of high energy phosphate, more recent studies have indicated a prominent role for the heat shock response. Observed modulations of injury by heat shock proteins in the immature kidney have significant implications for advancement of our understanding of renal cell injury in both adults and children.
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ABSTRACT: Tissues are equipped with reasonable strategies for repair and regeneration and the renal proximal tubule (PT) is no exception. New information has become available on the mode of PT regeneration in mammals. Unlike the intestinal epithelium with a high rate of turnover maintained by the stem cell system, the kidney has low turnover under normal physiological conditions. The PT seems to be maintained physiologically by hyperplasia, a regenerating system with self-renewal of mature tubular cells. This mode of regeneration is advantageous for effective replenishment of randomly isolated and eliminated tubular cells by self-renewal of adjacent cells. On the other hand, it has been suggested that dedifferentiation of mature tubular cells plays a role in regeneration after acute kidney injury. Recent studies employing genetic labeling and DNA-labeling techniques have confirmed that the proliferation of preexisting injured mature tubular cells contributes mainly to PT regeneration in ischemic reperfusion injury. This mode of regeneration is beneficial with regard to the rapid reparation of focally injured tubules often induced by ischemic reperfusion injury. What happens, however, when the PT is homogeneously injured with almost no remaining surviving cells Is the PT equipped with another backup regeneration system, e.g., the stem cell system Is it possible that certain types of renal injuries evoke a stem cell response whereas others do not This review focuses on all three possible modes of tissue regeneration (compensatory hyperplasia, dedifferentiation and stem cell system) in mammals and their involvement in PT regeneration in health and disease.World journal of nephrology. 08/2012; 1(4):92-9.
- American Journal Of Pathology 01/2009; 174(1):54-62. · 4.60 Impact Factor
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ABSTRACT: Hemopexin (Hpx) is a liver generated acute phase reactant that binds and neutralizes pro-oxidant free heme. This study tested whether AKI triggers renal Hpx accumulation, potentially impacting heme Fe mediated tubular injury. Mice were subjected to glycerol, cisplatin, ischemia-reperfusion (I/R), or endotoxemic (LPS) AKI. In each instance, 3-30 fold renal cortical and isolated proximal tubule segment (PTS) Hpx increases resulted. Although renal cortex and PTS showed variable Hpx mRNA increases, due, in part, to increased mRNA stability, mRNA levels did not correlate with renal Hpx protein accumulation. Conversely, AKI evoked 3-4 fold increases in hepatic Hpx gene induction which corresponded with 3-4 fold plasma Hpx increases. Renal immunohistochemistry, and increased urinary Hpx excretion, indicated that circulating Hpx gains tubule luminal/urinary access, followed by proximal tubule endocytic uptake. Paradoxically, in cultured renal cells (HK-2, HEK-293), Fe depletion, and not free heme excess, increased Hpx mRNA. LPS acutely increased HK-2 cell Hpx mRNA. This finding, coupled with observations that LPS evoked ~30 fold greater renal Hpx mRNA increases than any other AKI model, suggest that inflammation, not heme exposure, activates the renal Hpx gene. Each form of AKI evoked early increases in circulating free heme, which subsequently fell to subnormal levels as plasma Hpx rose. In addition, purified Hpx blunted free Fe mediated HK-2 cell death. In sum, these data indicated that AKI- associated hepatic stress generates Hpx which gains renal tubule access. Given its ability to bind free heme and mitigate free Fe toxicity, Hpx loading can potentially confer cytoprotective effects.AJP Renal Physiology 09/2012; · 4.42 Impact Factor