*5.3. Plant and Herb Derived Antioxidants*

Numerous plant- or herbal extracts or plant/herb-derived natural products have been tested for their capacity in fighting DKD. A major representative of these extracts is polyphenols that can scavenge ROS [177], leading to correction of redox imbalance and enhancement of mitochondrial function [178–180]. Moreover, these plants extracts can also activate the Nrf2 signaling pathway thereby leading to upregulation of the so-called second cellular defense system including antioxidant proteins such as heme oxygenase-1 and NQO1 [181]. As chronic inflammation is implicated in the pathogenesis of DKD, many studies involving plant extracts have also demonstrated their anti-inflammation properties in preclinical DKD [182]. Table 1 shows selected representatives of plant/herb extracts or plant/herb-derived compounds and their redox balanced-related anti-DKD mechanisms.


**Table 1.** Selected representatives of plant/herbal extracts/components in DKD from the literature. Experimental models and the major underlying renoprotective mechanisms are also given in the table.

\* Abbreviations: HFD, high fat diet; STZ, streptozotocin; ECM, extracellular matrix; MFG-E8, milk fat globule EGF-8. Please note that this table is not meant to exhaust the literature on plant/herbal extracts and DKD.

### *5.4. Caloric Restriction*

Caloric restriction (CR) [221–223], sometimes also called energy restriction [224,225], is a well-established approach for extending the lifespan of many species. CR can also prolong the health span of many organs including the kidney [226–229]. As CR has a direct impact on energy supply that involves NADH and NAD+, it thus is involved in eliciting antioxidative responses in DKD by restoring redox balance and mitigating diabetic kidney injury [230,231]. Such responses include AMPK activation, autophagy, ROS elimination, Nrf2 signaling pathway activation and enhancement of antioxidative capacity in the kidney [231–235]. In certain studies, exercise has been shown to have a synergistic effect on CR [236,237]. Therefore, CR and exercise may be applied simultaneously to enhance kidney function in diabetes [238,239]. Moreover, intermittent fasting, a different version of CR, has also been demonstrated to prevent progression of DKD via NAD+ dependent sirtuin pathway [230]. Additionally, the restriction of single element in a given diet such as iron can also afford renoprotection in diabetes via attenuation of oxidative stress [240].

#### **6. Magnitude of Redox Imbalance and Progression of DKD**

While it is now known that NADH/NAD<sup>+</sup> redox imbalance is one of the underlying mechanisms of DKD and this redox imbalance drives reductive stress to oxidative stress [47], culminating in renal dysfunction in DKD, whether the magnitude of NADH/NAD<sup>+</sup> redox imbalance can be associated with the indices of DKD progression has not been established. DKD progression can be determined by the ratio of urinary albumin to urinary creatinine [127] and by estimated glomerular flow rate (eGFR) [241,242], but whether NADH/NAD<sup>+</sup> ratio would also advance from low to high during DKD progression is unknown at this time and needs to be investigated. It is conceivable that with the progression of DKD quantitated by the above-mentioned parameters, values of the NADH/NAD<sup>+</sup> ratio would also increase gradually to reflect the severity of DKD. Conversely, the value of the NADH/NAD+ ratio should go down upon remission of DKD after treatment. Regardless, this would need to be evaluated using proper animal models that can show clearly an association of the value of NADH/NAD+ to progression of DKD until the end stage of renal disease.

#### **7. Conclusions**

NADH/NAD<sup>+</sup> redox imbalance, driven by persistent hyperglycemia and oversupply of other nutrients, is the initiator of reductive stress and oxidative stress in DKD [47]. More studies would be needed to dissect the role of each and every player in this cascade of redox imbalance biochemistry mechanism. Complete and comprehensive studies not only will shed insights into the mechanisms of DKD but will also facilitate identification of targets that can be explored for DKD therapy. As indicated in a recent review article by Matoba et al. [243], targeting NADH/NAD<sup>+</sup> redox imbalance would be a valuable approach for combating DKD. Finally, it should be pointed out that in terms of potential injury caused by redox imbalance, which part of the kidney or what type of cells that sustain the most damage have not been comprehensively evaluated. Therefore, future efforts should be made to assess redox imbalance-induced damage to endothelial cells of the renal vasculature, the podocytes and mesangial cells of the glomerulus and the epithelial cells of the tubule. Additionally, how redox imbalance differs within the tubule should also be measured.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The author's work was supported in part by UNTHSC seed grants RI10015 and RI10039.

**Conflicts of Interest:** The authors declare no conflict of interest.
